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Zhang Z, Gao Y, Qian Y, Wei B, Jiang K, Sun Z, Zhang F, Yang M, Baldi S, Yu X, Zuo Y, Ren S. The Lyn/RUVBL1 Complex Promotes Colorectal Cancer Liver Metastasis by Regulating Arachidonic Acid Metabolism Through Chromatin Remodeling. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2406562. [PMID: 39665272 PMCID: PMC11792055 DOI: 10.1002/advs.202406562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 11/26/2024] [Indexed: 12/13/2024]
Abstract
Liver metastasis is a common cause of death in colorectal cancer (CRC) patients, but epigenetic remodeling and metabolic reprogramming for CRC liver metastasis remain unclear. The study revealed that the Lyn/RUVBL1 complex is highly expressed in CRC and is closely correlated with liver metastasis. On the one hand, ATAC-seq and HiCut suggested that Lyn/RUVBL1 regulates the expression of TRIB3 through the POL II-mediated chromatin conformation of TRIB3 and thus the expression of β-catenin. This promotes the proliferation and migration of CRC through β-catenin-mediated upregulation of MMP9 and VEGF. On the other hand, metabolomics revealed that Lyn/RUVBL1 regulates the expression of PGE2 through the enzyme COX2, thereby promoting arachidonic acid (AA) metabolism. CUT-Tag showed that Lyn/RUVBL1 silencing reduces the H3K27ac level in the COX2 promoter. Then, it is found that COX2 is regulated by the transcription factor FOXA1. Lyn/RUVBL1 modulates AA metabolism by regulating the chromatin accessibility of FOXA1. AA metabolism promotes the metastasis of CRC by affecting β-catenin nuclear translocation and upregulating MMP9 and VEGF. These findings suggest that the Lyn/RUVBL1 complex mediates epigenetic remodeling to regulate the metabolic reprogramming of AA, highlighting its role in promoting the metastasis of CRC.
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Affiliation(s)
- Zhenyu Zhang
- Department of General SurgeryThe Second Hospital of Dalian Medical UniversityDalian116023China
- Department of Clinical BiochemistryCollege of Laoratory Medicine, Dalian Medical UniversityDalian116044China
| | - Yina Gao
- Department of General SurgeryThe Second Hospital of Dalian Medical UniversityDalian116023China
- Department of Clinical BiochemistryCollege of Laoratory Medicine, Dalian Medical UniversityDalian116044China
| | - Yuanyuan Qian
- Department of Clinical BiochemistryCollege of Laoratory Medicine, Dalian Medical UniversityDalian116044China
| | - Bowen Wei
- Department of Clinical BiochemistryCollege of Laoratory Medicine, Dalian Medical UniversityDalian116044China
| | - Kexin Jiang
- Department of Clinical BiochemistryCollege of Laoratory Medicine, Dalian Medical UniversityDalian116044China
| | - Zhiwei Sun
- Department of General SurgeryThe Second Hospital of Dalian Medical UniversityDalian116023China
| | - Feifan Zhang
- Department of General SurgeryThe Second Hospital of Dalian Medical UniversityDalian116023China
| | - Mingming Yang
- Department of Clinical BiochemistryCollege of Laoratory Medicine, Dalian Medical UniversityDalian116044China
| | - Salem Baldi
- Department of Clinical BiochemistryCollege of Laoratory Medicine, Dalian Medical UniversityDalian116044China
| | - Xiaoqi Yu
- Department of Clinical BiochemistryCollege of Laoratory Medicine, Dalian Medical UniversityDalian116044China
| | - Yunfei Zuo
- Department of Clinical BiochemistryCollege of Laoratory Medicine, Dalian Medical UniversityDalian116044China
| | - Shuangyi Ren
- Department of General SurgeryThe Second Hospital of Dalian Medical UniversityDalian116023China
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Aponte AMO, Ospina V, Pulido SA, Ríos-Vásquez LA, Jaramillo LAB, Peña CMM, Ocampo-Cardona R, Robledo SM. In Vitro Cytotoxicity of Fluorinated Quaternary Ammonium Salts in Colorectal Cancer Cells and In Silico Pharmacology. Adv Pharmacol Pharm Sci 2024; 2024:2671547. [PMID: 39512304 PMCID: PMC11540889 DOI: 10.1155/2024/2671547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 10/04/2024] [Indexed: 11/15/2024] Open
Abstract
Colorectal cancer (CRC) is a multifactorial disease driven by genetic and epigenetic alterations that modulate specific metabolic pathways. Despite the availability of effective treatments like 5-fluorouracil (5-FU), pharmacological therapy for CRC still faces significant challenges, including drug resistance, toxicity, and limited specificity. Therefore, discovering new compounds remains critical to overcoming these barriers and expanding treatment options. This study evaluated the cytotoxicity of fluorinated quaternary ammonium salts (FQAS) library in CRC-derived cell lines with premetastatic and metastatic phenotypes. The genetic and epigenetic background of the CRC cell lines and the selectivity of cytotoxicity compared to nontumor cells and between different CRC stages were also assessed. Additionally, the in silico pharmacological properties of these FQASs were analyzed. Results showed that FQASs 9-14 exhibited significant cytotoxic activity against both premetastatic and metastatic CRC cell lines, with FQASs 9, 13, and 14 displaying selective toxicity toward CRC cells over normal murine colorectal cells. However, in silico studies indicated poor oral bioavailability for these compounds, suggesting that an injection-based delivery route may be more effective for targeting CRC cells. In conclusion, CF3-containing FQASs are promising therapeutic candidates for CRC treatment.
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Affiliation(s)
| | - Victoria Ospina
- Grupo Estudios Preclínicos, Corporación de Innovación para el Desarrollo de Productos, Medellín, Colombia
| | - Sergio A. Pulido
- PECET-Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
- División I+D+i, LifeFactors Zona Franca S.A.S, Rionegro, Colombia
| | - Luz Amalia Ríos-Vásquez
- Química Teórica y Bioinformática, Departamento de Química, Universidad de Caldas, Manizales, Colombia
| | | | | | - Rogelio Ocampo-Cardona
- Química Teórica y Bioinformática, Departamento de Química, Universidad de Caldas, Manizales, Colombia
| | - Sara M. Robledo
- PECET-Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
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Johansen AM, Forsythe SD, McGrath CT, Barker G, Jimenez H, Paluri RK, Pasche BC. TGFβ in Pancreas and Colorectal Cancer: Opportunities to Overcome Therapeutic Resistance. Clin Cancer Res 2024; 30:3676-3687. [PMID: 38916900 PMCID: PMC11371528 DOI: 10.1158/1078-0432.ccr-24-0468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 04/16/2024] [Accepted: 05/30/2024] [Indexed: 06/26/2024]
Abstract
TGFβ is a pleiotropic signaling pathway that plays a pivotal role in regulating a multitude of cellular functions. TGFβ has a dual role in cell regulation where it induces growth inhibition and cell death; however, it can switch to a growth-promoting state under cancerous conditions. TGFβ is upregulated in colorectal cancer and pancreatic cancer, altering the tumor microenvironment and immune system and promoting a mesenchymal state. The upregulation of TGFβ in certain cancers leads to resistance to immunotherapy, and attempts to inhibit TGFβ expression have led to reduced therapeutic resistance when combined with chemotherapy and immunotherapy. Here, we review the current TGFβ inhibitor drugs in clinical trials for pancreatic and colorectal cancer, with the goal of uncovering advances in improving clinical efficacy for TGFβ combinational treatments in patients. Furthermore, we discuss the relevance of alterations in TGFβ signaling and germline variants in the context of personalizing treatment for patients who show lack of response to current therapeutics.
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Affiliation(s)
- Allan M. Johansen
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157-1082, USA
| | - Steven D. Forsythe
- Neuroendocrine Therapy Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Callum T. McGrath
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157-1082, USA
| | - Grayson Barker
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157-1082, USA
| | - Hugo Jimenez
- Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA
| | - Ravi K. Paluri
- Section of Hematology/Oncology, Wake Forest School of Medicine, Winston-Salem, NC, 27157-1082. USA
| | - Boris C. Pasche
- Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA
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Yang S, Zhang D, Sun Q, Nie H, Zhang Y, Wang X, Huang Y, Sun Y. Single-Cell and Spatial Transcriptome Profiling Identifies the Transcription Factor BHLHE40 as a Driver of EMT in Metastatic Colorectal Cancer. Cancer Res 2024; 84:2202-2217. [PMID: 38657117 DOI: 10.1158/0008-5472.can-23-3264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 02/14/2024] [Accepted: 04/18/2024] [Indexed: 04/26/2024]
Abstract
Colorectal cancer is one of the most common malignant tumors in humans, with liver metastasis being the primary cause of mortality. The epithelial-mesenchymal transition (EMT) process endows cancer cells with enhanced metastatic potential. To elucidate the cellular mechanisms driving EMT in colorectal cancer, we analyzed single-cell RNA sequencing data from 11 nonmetastatic primary tumors (TnM) and 11 metastatic primary tumors (TM) from colorectal cancer patients. Compared with the TnM group, the TM samples showed elevated numbers of malignant epithelial cell and cancer-associated fibroblast (CAF) subsets that displayed enrichments of EMT, angiogenesis, and TGFβ signaling pathways. One specific TM-enriched subgroup of malignant epithelial cells underwent EMT to transdifferentiate into CXCL1+ CAFs that subsequently differentiated into SFRP2+ CAFs, which was validated by spatial transcriptomic and pseudotime trajectory analyses. Furthermore, cell-cell communication analysis identified BHLHE40 as a probable key transcription factor driving EMT that was associated with poor prognosis. Finally, in vitro and in vivo experiments functionally substantiated that BHLHE40 promoted the proliferation, invasion, migration, EMT, and liver metastasis of colorectal cancer cells. In summary, this study identified BHLHE40 as a key transcription factor regulating EMT that promotes liver metastasis in colorectal cancer. Significance: Integrated analysis of single-cell RNA sequencing and spatial transcriptomics in metastatic colorectal cancer provides insights into the mechanisms underlying EMT and cancer-associated fibroblast differentiation, which could help improve patient diagnosis and treatment.
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Affiliation(s)
- Sheng Yang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- The Colorectal Institute of Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China
| | - Dongsheng Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- The Colorectal Institute of Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China
| | - Qingyang Sun
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- The Colorectal Institute of Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China
| | - Hongxu Nie
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- The Colorectal Institute of Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China
| | - Yue Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- The Colorectal Institute of Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China
| | - Xiaowei Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- The Colorectal Institute of Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China
| | - Yuanjian Huang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- The Colorectal Institute of Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China
| | - Yueming Sun
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
- The Colorectal Institute of Nanjing Medical University, Nanjing, China
- Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, China
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Sritharan S, Sivalingam N. Doxorubicin-induced chemoresistance in Duke's type B colon adenocarcinoma cell line is aggravated in the presence of TGF-β2 through non-apoptotic cell death. Clin Transl Oncol 2024; 26:1630-1638. [PMID: 38308764 DOI: 10.1007/s12094-023-03380-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 12/24/2023] [Indexed: 02/05/2024]
Abstract
BACKGROUND The current challenge in clinical cancer treatment is chemoresistance. Colon cells have inherently higher xenobiotic transporters expression and hence can attain resistance rapidly. Increased levels of TGF-β2 expression in patients have been attributed to cancer progression, aggressiveness, and resistance. To investigate resistance progression, we treated doxorubicin (dox) to HT-29 colon adenocarcinoma cells in the presence or absence of TGF-β2 ligand. METHODS After 1, 3-, and 7-day treatment, we investigated cell proliferation, viability, and cytotoxicity by MTT, trypan blue staining, and lactate dehydrogenase enzyme release. The mechanism of cell death was elucidated by hoechst33342 and propidium iodide dual staining and apoptosis assay. The development of resistance was detected by rhodamine123 efflux and P-glycoprotein (P-gp)/MDR1 antibody staining through fluorimetry and flow cytometry. The colony formation ability of the cells was also elucidated. RESULTS Inhibition of cell proliferation was noted after day 1, while a significant reduction in viability and a significant increase in lactate dehydrogenase release was detected after day 3. Reduction of intracellular rhodamine123 levels was detected after day 3 and was significantly lower in dox with TGF-β2 treatment compared to dox alone. Increased surface P-gp levels after days 3 and 7 were observed in the treated groups. Hoechst33342/propidium iodide staining and apoptosis assay indicated non-apoptotic cell death. The cells treated with TGF-β2 had higher colony formation ability. CONCLUSIONS TGF-β2 expression might play a significant role in the development of chemoresistance to doxorubicin in Duke's type B colon adenocarcinoma cell line, HT-29.
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Affiliation(s)
- Sruthi Sritharan
- Department of Biotechnology, School of Bioengineering, College of Engineering and Technology, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India
| | - Nageswaran Sivalingam
- Department of Biotechnology, School of Bioengineering, College of Engineering and Technology, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India.
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Wu Y, Yu B, Ai X, Zhang W, Chen W, Laurence A, Zhang M, Chen Q, Shao Y, Zhang B. TIF1γ and SMAD4 regulation in colorectal cancer: impact on cell proliferation and liver metastasis. Biol Chem 2024; 405:241-256. [PMID: 38270141 DOI: 10.1515/hsz-2023-0233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 12/13/2023] [Indexed: 01/26/2024]
Abstract
We investigated the effects of transcriptional intermediary factor 1γ (TIF1γ) and SMAD4 on the proliferation and liver metastasis of colorectal cancer (CRC) cells through knockdown of TIF1γ and/or SMAD4 and knockdown of TIF1γ and/or restoration of SMAD4 expression. Furthermore, we examined TIF1γ and SMAD4 expression in human primary CRC and corresponding liver metastatic CRC specimens. TIF1γ promoted but SMAD4 inhibited the proliferation of CRC cells by competitively binding to activated SMAD2/SMAD3 complexes and then reversely regulating c-Myc, p21, p27, and cyclinA2 levels. Surprisingly, both TIF1γ and SMAD4 reduced the liver metastasis of all studied CRC cell lines via inhibition of MEK/ERK pathway-mediated COX-2, Nm23, uPA, and MMP9 expression. In patients with advanced CRC, reduced TIF1γ or SMAD4 expression was correlated with increased invasion and liver metastasis and was a significant, independent risk factor for recurrence and survival after radical resection. Patients with advanced CRC with reduced TIF1γ or SAMD4 expression had higher recurrence rates and shorter overall survival. TIF1γ and SMAD4 competitively exert contrasting effects on cell proliferation but act complementarily to suppress the liver metastasis of CRC via MEK/ERK pathway inhibition. Thus, reduced TIF1γ or SMAD4 expression in advanced CRC predicts earlier liver metastasis and poor prognosis.
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Affiliation(s)
- Yanhui Wu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, China
| | - Bin Yu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Xi Ai
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, China
| | - Wei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, China
| | - Weixun Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, China
| | - Arian Laurence
- Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Mingzhi Zhang
- Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37235, USA
| | - Qian Chen
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, HUST, 1095 Jiefang Ave, Wuhan 430030, China
| | - Yajie Shao
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, HUST, 1095 Jiefang Ave, Wuhan 430030, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, China
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Al-Balushi E, Al Marzouqi A, Tavoosi S, Baghsheikhi AH, Sadri A, Aliabadi LS, Salarabedi MM, Rahman SA, Al-Yateem N, Jarrahi AM, Halimi A, Ahmadvand M, Abdel-Rahman WM. Comprehensive analysis of the role of ubiquitin-specific peptidases in colorectal cancer: A systematic review. World J Gastrointest Oncol 2024; 16:197-213. [PMID: 38292842 PMCID: PMC10824112 DOI: 10.4251/wjgo.v16.i1.197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 11/05/2023] [Accepted: 12/07/2023] [Indexed: 01/11/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the third most frequent and the second most fatal cancer. The search for more effective drugs to treat this disease is ongoing. A better understanding of the mechanisms of CRC development and progression may reveal new therapeutic strategies. Ubiquitin-specific peptidases (USPs), the largest group of the deubiquitinase protein family, have long been implicated in various cancers. There have been numerous studies on the role of USPs in CRC; however, a comprehensive view of this role is lacking. AIM To provide a systematic review of the studies investigating the roles and functions of USPs in CRC. METHODS We systematically queried the MEDLINE (via PubMed), Scopus, and Web of Science databases. RESULTS Our study highlights the pivotal role of various USPs in several processes implicated in CRC: Regulation of the cell cycle, apoptosis, cancer stemness, epithelial-mesenchymal transition, metastasis, DNA repair, and drug resistance. The findings of this study suggest that USPs have great potential as drug targets and noninvasive biomarkers in CRC. The dysregulation of USPs in CRC contributes to drug resistance through multiple mechanisms. CONCLUSION Targeting specific USPs involved in drug resistance pathways could provide a novel therapeutic strategy for overcoming resistance to current treatment regimens in CRC.
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Affiliation(s)
- Eman Al-Balushi
- College of Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Amina Al Marzouqi
- College of Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Shima Tavoosi
- Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan 81746-73441, Iran
| | - Amir Hossein Baghsheikhi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran 11365/4435, Iran
| | - Arash Sadri
- Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran 1416634793, Iran
| | - Leyla Sharifi Aliabadi
- Cell Therapy and Hematopoietic Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology, and Cell Therapy, Tehran University of Medical Sciences, Tehran 1416634793, Iran
| | - Mohammad-Mahdi Salarabedi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1983969411, Iran
| | - Syed Azizur Rahman
- College of Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Nabeel Al-Yateem
- Department of Nursing, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Alireza Mosavi Jarrahi
- Cancer Research Centre, Shahid Beheshti University of Medical Sciences, Tehran 1983969411, Iran
| | - Aram Halimi
- Cancer Research Centre, Shahid Beheshti University of Medical Sciences, Tehran 1983969411, Iran
| | - Mohammad Ahmadvand
- Cell Therapy and Hematopoietic Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology, and Cell Therapy, Tehran University of Medical Sciences , Tehran 1416634793, Iran
| | - Wael M Abdel-Rahman
- Department of Medical Laboratory Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
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Foley K, Shorthouse D, Rahrmann E, Zhuang L, Devonshire G, Gilbertson RJ, Fitzgerald RC, Hall BA. SMAD4 and KCNQ3 alterations are associated with lymph node metastases in oesophageal adenocarcinoma. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166867. [PMID: 37648039 DOI: 10.1016/j.bbadis.2023.166867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 08/25/2023] [Indexed: 09/01/2023]
Abstract
Metastasis in oesophageal adenocarcinoma (OAC) is an important predictor of survival. Radiological staging is used to stage metastases in patients, and guide treatment selection, but is limited by the accuracy of the approach. Improvements in staging will lead to improved clinical decision making and patient outcomes. Sequencing studies on primary tumours and pre-cancerous tissue have revealed the mutational landscape of OAC, and increasingly cheap and widespread sequencing approaches offer the potential to improve staging assessment. In this work we present an analysis of lymph node metastases found by radiological and pathological sampling, identifying new roles of the genes SMAD4 and KCNQ3 in metastasis. Through transcriptomic analysis we find that both genes are associated with canonical Wnt pathway activity, but KCNQ3 is uniquely associated with changes in planar cell polaritiy associated with non-canonical Wnt signalling. We go on to validate our observations in KCNQ3 in cell line and xenograph systems, showing that overexpression of KCNQ3 reduces wound closure and the number of metastases observed. Our results suggest both genes as novel biomarkers of metastatic risk and offer new potential routes to drug targeting.
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Affiliation(s)
- Kieran Foley
- Division of Cancer & Genetics, School of Medicine, Cardiff University, CF14 4XN, UK
| | | | - Eric Rahrmann
- Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE, UK
| | - Lizhe Zhuang
- Early Cancer Institute, University of Cambridge, CB2 0XZ, UK
| | | | | | | | - Benjamin A Hall
- Department of Medical Physics and Biomedical Engineering, University College London, WC1E 6BT, UK.
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9
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Tong K, Bandari M, Carrick JN, Zenkevich A, Kothari OA, Shamshad E, Stefanik K, Haro KS, Perekatt AO, Verzi MP. In Vitro Organoid-Based Assays Reveal SMAD4 Tumor-Suppressive Mechanisms for Serrated Colorectal Cancer Invasion. Cancers (Basel) 2023; 15:5820. [PMID: 38136364 PMCID: PMC10742020 DOI: 10.3390/cancers15245820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/08/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
Colon cancer is the third most prominent cancer and second leading cause of cancer-related deaths in the United States. Up to 20% of colon cancers follow the serrated tumor pathway driven by mutations in the MAPK pathway. Loss of SMAD4 function occurs in the majority of late-stage colon cancers and is associated with aggressive cancer progression. Therefore, it is important to develop technology to accurately model and better understand the genetic mechanisms behind cancer invasion. Organoids derived from tumors found in the Smad4KO BRAFV600E/+ mouse model present multiple phenotypes characteristic of invasion both in ex vivo and in vivo systems. Smad4KO BRAFV600E/+ tumor organoids can migrate through 3D culture and infiltrate through transwell membranes. This invasive behavior can be suppressed when SMAD4 is re-expressed in the tumor organoids. RNA-Seq analysis reveals that SMAD4 expression in organoids rapidly regulates transcripts associated with extracellular matrix and secreted proteins, suggesting that the mechanisms employed by SMAD4 to inhibit invasion are associated with regulation of extracellular matrix and secretory pathways. These findings indicate new models to study SMAD4 regulation of tumor invasion and an additional layer of complexity in the tumor-suppressive function of the SMAD4/Tgfβ pathway.
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Affiliation(s)
- Kevin Tong
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
- Human Genetics Institute of New Jersey, Piscataway, NJ 08854, USA
- Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
- Hackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USA
- Department of Medical Sciences, Hackensack Meridian Health School of Medicine, Nutley, NJ 07110, USA
| | - Manisha Bandari
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
| | - Jillian N. Carrick
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
- Hackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USA
| | - Anastasia Zenkevich
- Hackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USA
| | - Om A. Kothari
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
| | - Eman Shamshad
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
| | - Katarina Stefanik
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
- Department of Biology, The College of New Jersey, Ewing Township, NJ 08618, USA
| | - Katherine S. Haro
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
| | - Ansu O. Perekatt
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ 07030, USA
| | - Michael P. Verzi
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
- Human Genetics Institute of New Jersey, Piscataway, NJ 08854, USA
- Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
- Rutgers Center for Lipid Research, New Brunswick, NJ 08901, USA
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10
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Tian Y, Wang X, Cramer Z, Rhoades J, Estep KN, Ma X, Adams-Tzivelekidis S, Katona BW, Johnson FB, Yu Z, Blanco MA, Lengner CJ, Li N. APC and P53 mutations synergise to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer. Gut 2023; 72:2294-2306. [PMID: 37591698 PMCID: PMC10715527 DOI: 10.1136/gutjnl-2022-329140] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 07/30/2023] [Indexed: 08/19/2023]
Abstract
OBJECTIVE Colorectal cancer (CRC) is a leading cause of cancer-related deaths, with the majority of cases initiated by inactivation of the APC tumour suppressor. This results in the constitutive activation of canonical WNT pathway transcriptional effector ß-catenin, along with induction of WNT feedback inhibitors, including the extracellular palmitoleoyl-protein carboxylesterase NOTUM which antagonises WNT-FZD receptor-ligand interactions. Here, we sought to evaluate the effects of NOTUM activity on CRC as a function of driver mutation landscape. DESIGN Mouse and human colon organoids engineered with combinations of CRC driver mutations were used for Notum genetic gain-of-function and loss-of-function studies. In vitro assays, in vivo endoscope-guided orthotopic organoid implantation assays and transcriptomic profiling were employed to characterise the effects of Notum activity. Small molecule inhibitors of Notum activity were used in preclinical therapeutic proof-of-principle studies targeting oncogenic Notum activity. RESULTS NOTUM retains tumour suppressive activity in APC-null adenomas despite constitutive ß-catenin activity. Strikingly, on progression to adenocarcinoma with P53 loss, NOTUM becomes an obligate oncogene. These phenotypes are Wnt-independent, resulting from differential activity of NOTUM on glypican 1 and 4 in early-stage versus late-stage disease, respectively. Ultimately, preclinical mouse models and human organoid cultures demonstrate that pharmacological inhibition of NOTUM is highly effective in arresting primary adenocarcinoma growth and inhibiting metastatic colonisation of distal organs. CONCLUSIONS Our findings that a single agent targeting the extracellular enzyme NOTUM is effective in treating highly aggressive, metastatic adenocarcinomas in preclinical mouse models and human organoids make NOTUM and its glypican targets therapeutic vulnerabilities in advanced CRC.
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Affiliation(s)
- Yuhua Tian
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Xin Wang
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Zvi Cramer
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Joshua Rhoades
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Katrina N Estep
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Xianghui Ma
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Stephanie Adams-Tzivelekidis
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Bryson W Katona
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - F Brad Johnson
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Zhengquan Yu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - M Andres Blanco
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Christopher J Lengner
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Ning Li
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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11
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Kuburich NA, Sabapathy T, Demestichas BR, Maddela JJ, den Hollander P, Mani SA. Proactive and reactive roles of TGF-β in cancer. Semin Cancer Biol 2023; 95:120-139. [PMID: 37572731 PMCID: PMC10530624 DOI: 10.1016/j.semcancer.2023.08.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 08/04/2023] [Accepted: 08/05/2023] [Indexed: 08/14/2023]
Abstract
Cancer cells adapt to varying stress conditions to survive through plasticity. Stem cells exhibit a high degree of plasticity, allowing them to generate more stem cells or differentiate them into specialized cell types to contribute to tissue development, growth, and repair. Cancer cells can also exhibit plasticity and acquire properties that enhance their survival. TGF-β is an unrivaled growth factor exploited by cancer cells to gain plasticity. TGF-β-mediated signaling enables carcinoma cells to alter their epithelial and mesenchymal properties through epithelial-mesenchymal plasticity (EMP). However, TGF-β is a multifunctional cytokine; thus, the signaling by TGF-β can be detrimental or beneficial to cancer cells depending on the cellular context. Those cells that overcome the anti-tumor effect of TGF-β can induce epithelial-mesenchymal transition (EMT) to gain EMP benefits. EMP allows cancer cells to alter their cell properties and the tumor immune microenvironment (TIME), facilitating their survival. Due to the significant roles of TGF-β and EMP in carcinoma progression, it is essential to understand how TGF-β enables EMP and how cancer cells exploit this plasticity. This understanding will guide the development of effective TGF-β-targeting therapies that eliminate cancer cell plasticity.
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Affiliation(s)
- Nick A Kuburich
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Department of Pathology and Lab Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
| | - Thiru Sabapathy
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Department of Pathology and Lab Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
| | - Breanna R Demestichas
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Department of Pathology and Lab Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
| | - Joanna Joyce Maddela
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Department of Pathology and Lab Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
| | - Petra den Hollander
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Department of Pathology and Lab Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA
| | - Sendurai A Mani
- Legorreta Cancer Center, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA; Department of Pathology and Lab Medicine, The Warren Alpert Medical School, Brown University, Providence, RI 02912, USA.
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12
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Jiang ZY, Ma XM, Luan XH, Liuyang ZY, Hong YY, Dai Y, Dong QH, Wang GY. BMI-1 activates hepatic stellate cells to promote the epithelial-mesenchymal transition of colorectal cancer cells. World J Gastroenterol 2023; 29:3606-3621. [PMID: 37398890 PMCID: PMC10311613 DOI: 10.3748/wjg.v29.i23.3606] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/25/2023] [Accepted: 05/04/2023] [Indexed: 06/16/2023] Open
Abstract
BACKGROUND Activated hepatic stellate cells (aHSCs) are the major source of cancer-associated fibroblasts in the liver. Although the crosstalk between aHSCs and colorectal cancer (CRC) cells supports liver metastasis (LM), the mechanisms are largely unknown.
AIM To explore the role of BMI-1, a polycomb group protein family member, which is highly expressed in LM, and the interaction between aHSCs and CRC cells in promoting CRC liver metastasis (CRLM).
METHODS Immunohistochemistry was carried out to examine BMI-1 expression in LM and matched liver specimens of CRC. The expression levels of BMI-1 in mouse liver during CRLM (0, 7, 14, 21, and 28 d) were detected by Western blotting (WB) and the quantitative polymerase chain reaction (qPCR) assay. We overexpressed BMI-1 in HSCs (LX2) by lentivirus infection and tested the molecular markers of aHSCs by WB, qPCR, and the immunofluorescence assay. CRC cells (HCT116 and DLD1) were cultured in HSC-conditioned medium (LX2 NC CM or LX2 BMI-1 CM). CM-induced CRC cell proliferation, migration, epithelial-mesenchymal transition (EMT) phenotype, and transforming growth factor beta (TGF-β)/SMAD pathway changes were investigated in vitro. A mouse subcutaneous xenotransplantation tumor model was established by co-implantation of HSCs (LX2 NC or LX2 BMI-1) and CRC cells to investigate the effects of HSCs on tumor growth and the EMT phenotype in vivo.
RESULTS Positive of BMI-1 expression in the liver of CRLM patients was 77.8%. The expression level of BMI-1 continued to increase during CRLM in mouse liver cells. LX2 overexpressed BMI-1 was activated, accompanied by increased expression level of alpha smooth muscle actin, fibronectin, TGF-β1, matrix metalloproteinases, and interleukin 6. CRC cells cultured in BMI-1 CM exhibited enhanced proliferation and migration ability, EMT phenotype and activation of the TGF-β/SMAD pathway. In addition, the TGF-βR inhibitor SB-505124 diminished the effect of BMI-1 CM on SMAD2/3 phosphorylation in CRC cells. Furthermore, BMI-1 overexpressed LX2 HSCs promoted tumor growth and the EMT phenotype in vivo.
CONCLUSION High expression of BMI-1 in liver cells is associated with CRLM progression. BMI-1 activates HSCs to secrete factors to form a prometastatic environment in the liver, and aHSCs promote proliferation, migration, and the EMT in CRC cells partially through the TGF-β/SMAD pathway.
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Affiliation(s)
- Zhong-Yang Jiang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Xi-Mei Ma
- Department of Emergency, The Second Affiliated Hospital of Zhejing University, Hangzhou 310016, Zhejiang Province, China
| | - Xiao-Hui Luan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Zhen-Yu Liuyang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Yi-Yang Hong
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Yuan Dai
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Qing-Hua Dong
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou 310009, Zhejiang Province, China
| | - Guan-Yu Wang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
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13
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Turati M, Mousset A, Issa N, Turtoi A, Ronca R. TGF-β mediated drug resistance in solid cancer. Cytokine Growth Factor Rev 2023; 71-72:54-65. [PMID: 37100675 DOI: 10.1016/j.cytogfr.2023.04.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 04/09/2023] [Accepted: 04/10/2023] [Indexed: 04/28/2023]
Abstract
Transforming growth factor β (TGF-β) is an important signaling molecule which is expressed in three different isoforms in mammals (i.e. TGF-β1, -β2, and -β3). The interaction between TGF-β and its receptor triggers several pathways, which are classified into SMAD-dependent (canonical) and SMAD-independent (non-canonical) signaling, whose activation/transduction is finely regulated by several mechanisms. TGF-β is involved in many physiological and pathological processes, assuming a dualistic role in cancer progression depending on tumor stage. Indeed, TGF-β inhibits cell proliferation in early-stage tumor cells, while it promotes cancer progression and invasion in advanced tumors, where high levels of TGF-β have been reported in both tumor and stromal cells. In particular, TGF-β signaling has been found to be strongly activated in cancers after treatment with chemotherapeutic agents and radiotherapy, resulting in the onset of drug resistance conditions. In this review we provide an up-to-date description of several mechanisms involved in TGF-β-mediated drug resistance, and we report different strategies that are currently under development in order to target TGF-β pathway and increase tumor sensitivity to therapy.
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Affiliation(s)
- Marta Turati
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Alexandra Mousset
- Tumor Microenvironment and Resistance to Treatment Lab, Institut de Recherche en Cancérologie de Montpellier, INSERMU1194, Institut du Cancer de Montpellier, University of Montpellier, France
| | - Nervana Issa
- Tumor Microenvironment and Resistance to Treatment Lab, Institut de Recherche en Cancérologie de Montpellier, INSERMU1194, Institut du Cancer de Montpellier, University of Montpellier, France
| | - Andrei Turtoi
- Tumor Microenvironment and Resistance to Treatment Lab, Institut de Recherche en Cancérologie de Montpellier, INSERMU1194, Institut du Cancer de Montpellier, University of Montpellier, France.
| | - Roberto Ronca
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
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14
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Kumar A, Gautam V, Sandhu A, Rawat K, Sharma A, Saha L. Current and emerging therapeutic approaches for colorectal cancer: A comprehensive review. World J Gastrointest Surg 2023; 15:495-519. [PMID: 37206081 PMCID: PMC10190721 DOI: 10.4240/wjgs.v15.i4.495] [Citation(s) in RCA: 80] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 01/11/2023] [Accepted: 03/03/2023] [Indexed: 04/22/2023] Open
Abstract
Colorectal cancer (CRC) affects 1 in 23 males and 1 in 25 females, making it the third most common cancer. With roughly 608000 deaths worldwide, CRC accounts for 8% of all cancer-related deaths, making it the second most common cause of death due to cancer. Standard and conventional CRC treatments include surgical expurgation for resectable CRC and radiotherapy, chemotherapy, immunotherapy, and their combinational regimen for non-resectable CRC. Despite these tactics, nearly half of patients develop incurable recurring CRC. Cancer cells resist the effects of chemotherapeutic drugs in a variety of ways, including drug inactivation, drug influx and efflux modifications, and ATP-binding cassette transporter overexpression. These constraints necessitate the development of new target-specific therapeutic strategies. Emerging therapeutic approaches, such as targeted immune boosting therapies, non-coding RNA-based therapies, probiotics, natural products, oncolytic viral therapies, and biomarker-driven therapies, have shown promising results in preclinical and clinical studies. We tethered the entire evolutionary trends in the development of CRC treatments in this review and discussed the potential of new therapies and how they might be used in conjunction with conventional treatments as well as their advantages and drawbacks as future medicines.
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Affiliation(s)
- Anil Kumar
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Vipasha Gautam
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Arushi Sandhu
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Kajal Rawat
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Antika Sharma
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Lekha Saha
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
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15
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Ali S, Rehman MU, Yatoo AM, Arafah A, Khan A, Rashid S, Majid S, Ali A, Ali MN. TGF-β signaling pathway: Therapeutic targeting and potential for anti-cancer immunity. Eur J Pharmacol 2023; 947:175678. [PMID: 36990262 DOI: 10.1016/j.ejphar.2023.175678] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 03/07/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023]
Abstract
Transforming growth factor-β (TGFβ) is a pleiotropic secretory cytokine exhibiting both cancer-inhibitory and promoting properties. It transmits its signals via Suppressor of Mother against Decapentaplegic (SMAD) and non-SMAD pathways and regulates cell proliferation, differentiation, invasion, migration, and apoptosis. In non-cancer and early-stage cancer cells, TGFβ signaling suppresses cancer progression via inducing apoptosis, cell cycle arrest, or anti-proliferation, and promoting cell differentiation. On the other hand, TGFβ may also act as an oncogene in advanced stages of tumors, wherein it develops immune-suppressive tumor microenvironments and induces the proliferation of cancer cells, invasion, angiogenesis, tumorigenesis, and metastasis. Higher TGFβ expression leads to the instigation and development of cancer. Therefore, suppressing TGFβ signals may present a potential treatment option for inhibiting tumorigenesis and metastasis. Different inhibitory molecules, including ligand traps, anti-sense oligo-nucleotides, small molecule receptor-kinase inhibitors, small molecule inhibitors, and vaccines, have been developed and clinically trialed for blocking the TGFβ signaling pathway. These molecules are not pro-oncogenic response-specific but block all signaling effects induced by TGFβ. Nonetheless, targeting the activation of TGFβ signaling with maximized specificity and minimized toxicity can enhance the efficacy of therapeutic approaches against this signaling pathway. The molecules that are used to target TGFβ are non-cytotoxic to cancer cells but designed to curtail the over-activation of invasion and metastasis driving TGFβ signaling in stromal and cancer cells. Here, we discussed the critical role of TGFβ in tumorigenesis, and metastasis, as well as the outcome and the promising achievement of TGFβ inhibitory molecules in the treatment of cancer.
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16
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Huang J, Tan X, Liu Y, Jiang K, Luo J. Knockdown of UBE2I inhibits tumorigenesis and enhances chemosensitivity of cholangiocarcinoma via modulating p27kip1 nuclear export. Mol Carcinog 2023; 62:700-715. [PMID: 36825757 DOI: 10.1002/mc.23518] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 01/27/2023] [Accepted: 01/30/2023] [Indexed: 02/25/2023]
Abstract
The asymptomatic nature of cholangiocarcinoma (CCA), particularly during its early stages, in combination with its high aggressiveness and chemoresistance, significantly compromises the efficacy of current therapeutic options, contributing to a dismal prognosis. As a tumor suppressor that inhibits the cell cycle, abnormal cytoplasmic p27kip1 localization is related to chemotherapy resistance and often occurs in various cancers, including CCA. Nevertheless, the underlying mechanism is unclear. SUMOylation, which is involved in regulating subcellular localization and the cell cycle, is a posttranslational modification that regulates p27kip1 activity. Here, we confirmed that UBE2I, as the only key enzyme for SUMOylation, was highly expressed and p27kip1 was downregulated in CCA tissues, which were associated with poor outcomes in CCA. Moreover, UBE2I silencing inhibited CCA cell proliferation, delayed xenograft tumor growth in vivo, and sensitized CCA cells to the chemotherapeutics, which may be due to cell cycle arrest induced by p27kip1 nuclear accumulation. According to the immunoprecipitation result, we found that UBE2I could bind p27kip1, and the binding amount of p27kip1 and SUMO-1 decreased after UBE2I silencing. Moreover, nuclear retention of p27kip1 was induced by UBE2I knockdown and SUMOylation or CRM1 inhibition, further suggesting that UBE2I could cooperate with CRM1 in the nuclear export of p27kip1. These data indicate that UBE2I-mediated SUMOylation is a novel regulatory mechanism that underlies p27kip1 export and controls CCA tumorigenesis, providing a therapeutic option for CCA treatment.
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Affiliation(s)
- Jie Huang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Xiaolong Tan
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Yan Liu
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Kainian Jiang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Jian Luo
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
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17
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Groeneveldt C, van Ginkel JQ, Kinderman P, Sluijter M, Griffioen L, Labrie C, van den Wollenberg DJ, Hoeben RC, van der Burg SH, ten Dijke P, Hawinkels LJ, van Hall T, van Montfoort N. Intertumoral Differences Dictate the Outcome of TGF-β Blockade on the Efficacy of Viro-Immunotherapy. CANCER RESEARCH COMMUNICATIONS 2023; 3:325-337. [PMID: 36860656 PMCID: PMC9973387 DOI: 10.1158/2767-9764.crc-23-0019] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/03/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023]
Abstract
The absence of T cells in the tumor microenvironment of solid tumors is a major barrier to cancer immunotherapy efficacy. Oncolytic viruses, including reovirus type 3 Dearing (Reo), can recruit CD8+ T cells to the tumor and thereby enhance the efficacy of immunotherapeutic strategies that depend on high T-cell density, such as CD3-bispecific antibody (bsAb) therapy. TGF-β signaling might represent another barrier to effective Reo&CD3-bsAb therapy due to its immunoinhibitory characteristics. Here, we investigated the effect of TGF-β blockade on the antitumor efficacy of Reo&CD3-bsAb therapy in the preclinical pancreatic KPC3 and colon MC38 tumor models, where TGF-β signaling is active. TGF-β blockade impaired tumor growth in both KPC3 and MC38 tumors. Furthermore, TGF-β blockade did not affect reovirus replication in both models and significantly enhanced the Reo-induced T-cell influx in MC38 colon tumors. Reo administration decreased TGF-β signaling in MC38 tumors but instead increased TGF-β activity in KPC3 tumors, resulting in the accumulation of α-smooth muscle actin (αSMA+) fibroblasts. In KPC3 tumors, TGF-β blockade antagonized the antitumor effect of Reo&CD3-bsAb therapy, even though T-cell influx and activity were not impaired. Moreover, genetic loss of TGF-β signaling in CD8+ T cells had no effect on therapeutic responses. In contrast, TGF-β blockade significantly improved therapeutic efficacy of Reo&CD3-bsAb in mice bearing MC38 colon tumors, resulting in a 100% complete response. Further understanding of the factors that determine this intertumor dichotomy is required before TGF-β inhibition can be exploited as part of viroimmunotherapeutic combination strategies to improve their clinical benefit. Significance Blockade of the pleiotropic molecule TGF-β can both improve and impair the efficacy of viro-immunotherapy, depending on the tumor model. While TGF-β blockade antagonized Reo&CD3-bsAb combination therapy in the KPC3 model for pancreatic cancer, it resulted in 100% complete responses in the MC38 colon model. Understanding factors underlying this contrast is required to guide therapeutic application.
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Affiliation(s)
- Christianne Groeneveldt
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Jurriaan Q. van Ginkel
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Priscilla Kinderman
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Marjolein Sluijter
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Lisa Griffioen
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Camilla Labrie
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | | | - Rob C. Hoeben
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Sjoerd H. van der Burg
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Peter ten Dijke
- Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Lukas J.A.C. Hawinkels
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Thorbald van Hall
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Nadine van Montfoort
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.,Corresponding Author: Nadine van Montfoort, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, the Netherlands. Phone: 317-1526-4726; E-mail:
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18
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Tanjak P, Chaiboonchoe A, Suwatthanarak T, Acharayothin O, Thanormjit K, Chanthercrob J, Suwatthanarak T, Wannasuphaphol B, Chumchuen K, Suktitipat B, Sampattavanich S, Korphaisarn K, Pongpaibul A, Poungvarin N, Grove H, Riansuwan W, Trakarnsanga A, Methasate A, Pithukpakorn M, Chinswangwatanakul V. The KRAS-Mutant Consensus Molecular Subtype 3 Reveals an Immunosuppressive Tumor Microenvironment in Colorectal Cancer. Cancers (Basel) 2023; 15:cancers15041098. [PMID: 36831441 PMCID: PMC9953921 DOI: 10.3390/cancers15041098] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 02/11/2023] Open
Abstract
Colorectal cancers (CRC) with KRAS mutations (KRASmut) are frequently included in consensus molecular subtype 3 (CMS3) with profound metabolic deregulation. We explored the transcriptomic impact of KRASmut, focusing on the tumor microenvironment (TME) and pathways beyond metabolic deregulation. The status of KRASmut in patients with CRC was investigated and overall survival (OS) was compared with wild-type KRAS (KRASwt). Next, we identified CMS, and further investigated differentially expressed genes (DEG) of KRASmut and distinctive pathways. Lastly, we used spatially resolved gene expression profiling to define the effect of KRASmut in the TME regions of CMS3-classified CRC tissues. CRC patients with KRASmut were mainly enriched in CMS3. Their specific enrichments of immune gene signatures in immunosuppressive TME were associated with worse OS. Activation of TGFβ signaling by KRASmut was related to reduced pro-inflammatory and cytokine gene signatures, leading to suppression of immune infiltration. Digital spatial profiling in TME regions of KRASmut CMS3-classified tissues suggested up-regulated genes, CD40, CTLA4, ARG1, STAT3, IDO, and CD274, that could be characteristic of immune suppression in TME. This study may help to depict the complex transcriptomic profile of KRASmut in immunosuppressive TME. Future studies and clinical trials in CRC patients with KRASmut should consider these transcriptional landscapes.
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Affiliation(s)
- Pariyada Tanjak
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Wanglang Road, Bangkok 10700, Thailand
- Siriraj Cancer Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Amphun Chaiboonchoe
- Siriraj Center of Research Excellent for Systems Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Siriraj Genomics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Tharathorn Suwatthanarak
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Wanglang Road, Bangkok 10700, Thailand
| | - Onchira Acharayothin
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Wanglang Road, Bangkok 10700, Thailand
| | - Kullanist Thanormjit
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Wanglang Road, Bangkok 10700, Thailand
- Siriraj Cancer Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Jantappapa Chanthercrob
- Siriraj Center of Research Excellent for Systems Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Siriraj Genomics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Thanawat Suwatthanarak
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Wanglang Road, Bangkok 10700, Thailand
- Siriraj Cancer Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Bundit Wannasuphaphol
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Wanglang Road, Bangkok 10700, Thailand
| | - Kemmapon Chumchuen
- Siriraj Genomics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Bhoom Suktitipat
- Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Integrative Computational Bioscience Center, Mahidol University, Nakhon Pathom 73170, Thailand
- Division of Medical Bioinformatics, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Somponnat Sampattavanich
- Siriraj Center of Research Excellent for Systems Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Siriraj Genomics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Krittiya Korphaisarn
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Ananya Pongpaibul
- Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Naravat Poungvarin
- Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Harald Grove
- Division of Medical Bioinformatics, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Woramin Riansuwan
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Wanglang Road, Bangkok 10700, Thailand
| | - Atthaphorn Trakarnsanga
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Wanglang Road, Bangkok 10700, Thailand
| | - Asada Methasate
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Wanglang Road, Bangkok 10700, Thailand
| | - Manop Pithukpakorn
- Siriraj Genomics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Division of Medical Genetics, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Vitoon Chinswangwatanakul
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Wanglang Road, Bangkok 10700, Thailand
- Siriraj Cancer Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Correspondence:
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ATOH8 binds SMAD3 to induce cellular senescence and prevent Ras-driven malignant transformation. Proc Natl Acad Sci U S A 2023; 120:e2208927120. [PMID: 36626550 PMCID: PMC9934021 DOI: 10.1073/pnas.2208927120] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
The process of oncogene-induced senescence (OIS) and the conversion between OIS and malignant transformation during carcinogenesis is poorly understood. Here, we show that following overactivation of oncogene Ras in lung epithelial cells, high-level transforming growth factor β1 (TGF-β1)-activated SMAD3, but not SMAD2 or SMAD4, plays a determinant role in inducing cellular senescence independent of the p53/p16/p15 senescence pathways. Importantly, SMAD3 binds a potential tumor suppressor ATOH8 to form a transcriptional complex that directly represses a series of cell cycle-promoting genes and consequently causes senescence in lung epithelial cells. Interestingly, the prosenescent SMAD3 converts to being oncogenic and essentially facilitates oncogenic Ras-driven malignant transformation. Furthermore, depleting Atoh8 rapidly accelerates oncogenic Ras-driven lung tumorigenesis, and lung cancers driven by mutant Ras and Atoh8 loss, but not by mutant Ras only, are sensitive to treatment of a specific SMAD3 inhibitor. Moreover, hypermethylation of the ATOH8 gene can be found in approximately 12% of clinical lung cancer cases. Together, our findings demonstrate not only epithelial cellular senescence directed by a potential tumor suppressor-controlled transcriptional program but also an important interplay between the prosenescent and transforming effects of TGF-β/SMAD3, potentially laying a foundation for developing early detection and anticancer strategies.
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An HW, Seok SH, Kwon JW, Choudhury AD, Oh JS, Voon DC, Kim DY, Park JW. The loss of epithelial Smad4 drives immune evasion via CXCL1 while displaying vulnerability to combinatorial immunotherapy in gastric cancer. Cell Rep 2022; 41:111878. [PMID: 36577366 DOI: 10.1016/j.celrep.2022.111878] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 10/17/2022] [Accepted: 12/02/2022] [Indexed: 12/29/2022] Open
Abstract
SMAD4 is frequently mutated and inactivated in human gastric cancer (GC). Although the epithelial cell-autonomous functions of Smad4 have been extensively studied, its contribution to tumor immunity is largely undetermined. Here, we report that the loss of Smad4 expression in GC cells endows them with the ability to evade tumor immunity. Unlike their Smad4-proficient counterparts, Smad4-deficient stomach organoids can evade host immunity to form tumors in immunocompetent mice. Smad4-deficient GC cells show expanded CD133+ cancer stem-like cells while suppressing dendritic cell (DC) differentiation and cytotoxic T cells with granulocytic myeloid-derived suppressor cell (G-MDSC) accumulation through a secretome containing CXCL1. Moreover, Smad4 deficiency increases programmed cell death ligand-1 (PD-L1) and decreases 4-1BBL expressions, indicating a change in immunogenicity. Combinatorial immune checkpoint blockade (ICB) of anti-PD-L1 and anti-CTLA-4 or agonistic anti-4-1BB antibodies effectively treats ICB monotherapy-resistant Smad4-deficient allografts, exposing a specific vulnerability. Collectively, these data provide a rational basis for ICB strategies in treating advanced GC with Smad4 deficiency.
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Affiliation(s)
- Hyeok-Won An
- Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, 1 Kangwondaehak-gil, ChunCheon-si, Gangwon-do 24341, South Korea
| | - Sang Hyeok Seok
- Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, 1 Kangwondaehak-gil, ChunCheon-si, Gangwon-do 24341, South Korea
| | - Jong-Wan Kwon
- Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, 1 Kangwondaehak-gil, ChunCheon-si, Gangwon-do 24341, South Korea
| | - Anahita Dev Choudhury
- Innovative Cancer Model Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Jeong-Seop Oh
- Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, South Korea
| | - Dominic C Voon
- Innovative Cancer Model Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan; Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
| | - Dae-Yong Kim
- Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, South Korea.
| | - Jun Won Park
- Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, 1 Kangwondaehak-gil, ChunCheon-si, Gangwon-do 24341, South Korea.
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21
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Timofeeva AV, Asaturova AV, Sannikova MV, Khabas GN, Chagovets VV, Fedorov IS, Frankevich VE, Sukhikh GT. Search for New Participants in the Pathogenesis of High-Grade Serous Ovarian Cancer with the Potential to Be Used as Diagnostic Molecules. LIFE (BASEL, SWITZERLAND) 2022; 12:life12122017. [PMID: 36556382 PMCID: PMC9784419 DOI: 10.3390/life12122017] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/25/2022] [Accepted: 12/01/2022] [Indexed: 12/11/2022]
Abstract
Recent studies have attempted to develop molecular signatures of epithelial ovarian cancer (EOC) based on the quantitation of protein-coding and non-coding RNAs to predict disease prognosis. Due to the heterogeneity of EOC, none of the developed prognostic signatures were directly applied in clinical practice. Our work focuses on high-grade serous ovarian carcinoma (HGSOC) due to the highest mortality rate relative to other types of EOC. Using deep sequencing of small non-coding RNAs in combination with quantitative real-time PCR, we confirm the dualistic classification of epithelial ovarian cancers based on the miRNA signature of HGSOC (type 2), which differs from benign cystadenoma and borderline cystadenoma-precursors of low-grade serous ovarian carcinoma (type 1)-and identified two subtypes of HGSOC, which significantly differ in the level of expression of the progesterone receptor in the tumor tissue, the secretion of miR-16-5p, miR-17-5p, miR-93-5p, miR-20a-5p, the level of serum CA125, tumor size, surgical outcome (optimal or suboptimal cytoreduction), and response to chemotherapy. It was found that the combined determination of the level of miR-16-5p, miR-17-5p, miR-20a-5p, and miR-93-5p circulating in blood plasma of patients with primary HGSOC tumors makes it possible to predict optimal cytoreduction with 80.1% sensitivity and 70% specificity (p = 0.022, TPR = 0.8, FPR = 0.3), as well as complete response to adjuvant chemotherapy with 77.8% sensitivity and 90.9% specificity (p = 0.001, TPR = 0.78, FPR = 0.09). After the additional verification of the obtained data in a larger HGSOC patient cohort, the combined quantification of these four miRNAs is proposed to be used as a criterion for selecting patients either for primary cytoreduction or neoadjuvant chemotherapy followed by interval cytoreduction.
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Affiliation(s)
- Angelika V. Timofeeva
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of The Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia
- Correspondence: or ; Tel.: +7-495-531-4444
| | - Aleksandra V. Asaturova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of The Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia
| | - Maya V. Sannikova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of The Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia
| | - Grigory N. Khabas
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of The Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia
| | - Vitaliy V. Chagovets
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of The Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia
| | - Ivan S. Fedorov
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of The Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia
| | - Vladimir E. Frankevich
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of The Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia
- Laboratory of Translational Medicine, Siberian State Medical University, 634050 Tomsk, Russia
| | - Gennady T. Sukhikh
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of The Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia
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22
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Ward TM, Cauley CE, Stafford CE, Goldstone RN, Bordeianou LG, Kunitake H, Berger DL, Ricciardi R. Tumour genotypes account for survival differences in right- and left-sided colon cancers. Colorectal Dis 2022; 24:601-610. [PMID: 35142008 DOI: 10.1111/codi.16060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 12/11/2021] [Accepted: 12/14/2021] [Indexed: 02/08/2023]
Abstract
AIM We sought to identify genetic differences between right- and left-sided colon cancers and using these differences explain lower survival in right-sided cancers. METHOD A retrospective review of patients diagnosed with colon cancer was performed using The Cancer Genome Atlas, a cancer genetics registry with patient and tumour data from 20 North American institutions. The primary outcome was 5-year overall survival. Predictors for survival were identified using directed acyclic graphs and Cox proportional hazards models. RESULTS A total of 206 right- and 214 left-sided colon cancer patients with 84 recorded deaths were identified. The frequency of mutated alleles differed significantly in 12 of 25 genes between right- and left-sided tumours. Right-sided tumours had worse survival with a hazard ratio of 1.71 (95% confidence interval 1.10-2.64, P = 0.017). The total effect of the genetic loci on survival showed five genes had a sizeable effect on survival: DNAH5, MUC16, NEB, SMAD4, and USH2A. Lasso-penalized Cox regression selected 13 variables for the highest-performing model, which included cancer stage, positive resection margin, and mutated alleles at nine genes: MUC16, USH2A, SMAD4, SYNE1, FLG, NEB, TTN, OBSCN, and DNAH5. Post-selection inference demonstrated that mutations in MUC16 (P = 0.01) and DNAH5 (P = 0.02) were particularly predictive of 5-year overall survival. CONCLUSIONS Our study showed that genetic mutations may explain survival differences between tumour sites. Further studies on larger patient populations may identify other genes, which could form the foundation for more precise prognostication and treatment decisions beyond current rudimentary TNM staging.
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Affiliation(s)
- Thomas M Ward
- Section of Colon and Rectal Surgery, Division of General and Gastrointestinal Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Christy E Cauley
- Section of Colon and Rectal Surgery, Division of General and Gastrointestinal Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Caitlin E Stafford
- Section of Colon and Rectal Surgery, Division of General and Gastrointestinal Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Robert N Goldstone
- Section of Colon and Rectal Surgery, Division of General and Gastrointestinal Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Liliana G Bordeianou
- Section of Colon and Rectal Surgery, Division of General and Gastrointestinal Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Hiroko Kunitake
- Section of Colon and Rectal Surgery, Division of General and Gastrointestinal Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - David L Berger
- Section of Colon and Rectal Surgery, Division of General and Gastrointestinal Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Rocco Ricciardi
- Section of Colon and Rectal Surgery, Division of General and Gastrointestinal Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
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Youssef ASED, Abdel-Fattah MA, Lotfy MM, Nassar A, Abouelhoda M, Touny AO, Hassan ZK, Mohey Eldin M, Bahnassy AA, Khaled H, Zekri ARN. Multigene Panel Sequencing Reveals Cancer-Specific and Common Somatic Mutations in Colorectal Cancer Patients: An Egyptian Experience. Curr Issues Mol Biol 2022; 44:1332-1352. [PMID: 35723313 PMCID: PMC8947625 DOI: 10.3390/cimb44030090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 02/22/2022] [Accepted: 02/25/2022] [Indexed: 12/11/2022] Open
Abstract
This study aims at identifying common pathogenic somatic mutations at different stages of colorectal carcinogenesis in Egyptian patients. Our cohort included colonoscopic biopsies collected from 120 patients: 20 biopsies from patients with inflammatory bowel disease, 38 from colonic polyp patients, and 62 from patients with colorectal cancer. On top of this, the cohort included 20 biopsies from patients with non-specific mild to moderated colitis. Targeted DNA sequencing using a customized gene panel of 96 colorectal related genes running on the Ion Torrent NGS technology was used to process the samples. Our results revealed that 69% of all cases harbored at least one somatic mutation. Fifty-seven genes were found to carry 232 somatic non-synonymous variants. The most frequently pathogenic somatic mutations were localized in TP53, APC, KRAS, and PIK3CA. In total, 16 somatic mutations were detected in the CRC group and in either the IBD or CP group. In addition, our data showed that 51% of total somatic variants were CRC-specific variants. The average number of CRC-specific variants per sample is 2.4. The top genes carrying CRC-specific mutations are APC, TP53, PIK3CA, FBXW7, ATM, and SMAD4. It seems obvious that TP53 and APC genes were the most affected genes with somatic mutations in all groups. Of interest, 85% and 28% of the APC and TP53 deleterious somatic mutations were located in Exon 14 and Exon 3, respectively. Besides, 37% and 28% of the total somatic mutations identified in APC and TP53 were CRC-specific variants, respectively. Moreover, we identified that, in 29 somatic mutations in 21 genes, their association with CRC patients was unprecedented. Ten detected variants were likely to be novel: six in PIK3CA and four variants in FBXW7. The detected P53, Wnt/βcatenin, Angiogenesis, EGFR, TGF-β and Interleukin signaling pathways were the most altered pathways in 22%, 16%, 12%, 10%, 9% and 9% of the CRC patients, respectively. These results would contribute to a better understanding of the colorectal cancer and in introducing personalized therapies for Egyptian CRC patients.
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Affiliation(s)
- Amira Salah El-Din Youssef
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt; (M.M.L.); (A.N.); (Z.K.H.)
| | | | - Mai M. Lotfy
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt; (M.M.L.); (A.N.); (Z.K.H.)
| | - Auhood Nassar
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt; (M.M.L.); (A.N.); (Z.K.H.)
| | | | - Ahmed O. Touny
- Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt;
| | - Zeinab K. Hassan
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt; (M.M.L.); (A.N.); (Z.K.H.)
| | - Mohammed Mohey Eldin
- Tropical Medicine Department, El Kasr Al-Aini, Cairo University, Cairo 11562, Egypt;
| | - Abeer A. Bahnassy
- Molecular Pathology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt;
| | - Hussein Khaled
- Medical Oncology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt;
| | - Abdel Rahman N. Zekri
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt; (M.M.L.); (A.N.); (Z.K.H.)
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24
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Xu Z, Gao H, Zhang Y, Feng W, Miao Y, Xu Z, Li W, Chen F, Lv Z, Huo J, Liu W, Shen X, Zong Y, Zhao J, Lu A. CCL7 and TGF-β secreted by MSCs play opposite roles in regulating CRC metastasis in a KLF5/CXCL5 dependent manner. Mol Ther 2022; 30:2327-2341. [DOI: 10.1016/j.ymthe.2022.03.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 01/12/2022] [Accepted: 03/07/2022] [Indexed: 11/29/2022] Open
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25
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Sun X, Xue Z, Yasin A, He Y, Chai Y, Li J, Zhang K. Colorectal Cancer and Adjacent Normal Mucosa Differ in Apoptotic and Inflammatory Protein Expression. ENGINEERED REGENERATION 2022. [DOI: 10.1016/j.engreg.2022.01.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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26
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Su H, Wang C. Prognostic value of SMAD4 in resectable pancreatic cancer. POSTEP HIG MED DOSW 2022; 76:324-332. [DOI: 10.2478/ahem-2022-0036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Abstract
Introduction
The tumor gene SMAD4 was genetically inactivated in approximately half of pancreatic cancer (PC) patients. The correlation of SMAD4 gene expression in PC and its prognosis remains inconclusive. The aim of this study was to evaluate the association between loss of SMAD4 expression and the outcome of resectable PC.
Materials and Methods
A systematic review of the relevant electronic databases was conducted between SMAD4 expression and the outcome of PC patients until December 2020, including PubMed, Web of Science, and the China Journal Net. A meta-analysis was performed using STATA 12.0 and pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate the strength of the association between SMAD4 gene expression and the prognosis of PC patients.
Results
Twelve studies were included. Our meta-analysis illustrated that there were no significant associations between the loss of SMAD4 gene expression and overall survival in resectable PC (HR=1.38, 95% CI 0.98–1.81). In addition, there was no evidence of publication bias, as showed by Begg's and Egger's test. There was no correlation between the loss of SMAD4 expression and local recurrence (OR=0.97, 95% CI 0.52–1.80, p=0.914), while the loss of SMAD4 gene expression was associated with increased risk of distant recurrence (OR=1.36, 95% CI 1.08–1.70, p=0.008).
Conclusions
After PC resection, the loss of SMAD4 gene expression was correlated with higher risk of distant recurrence, but not with local recurrence nor overall survival.
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Affiliation(s)
- Hui Su
- Department of Gastrointestinal Surgery , First Affiliated Hospital of Jinan University , Guangzhou , China
- Department of General Surgery, Hwa Mei Hospital , University of Chinese Academy of Sciences , Ningbo , China
- Ningbo Institute of Life and Health Industry , University of Chinese Academy of Sciences
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province
| | - Cunchuan Wang
- Department of Gastrointestinal Surgery , First Affiliated Hospital of Jinan University , Guangzhou , China
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Lohani S, Funato Y, Akieda Y, Mizutani K, Takai Y, Ishitani T, Miki H. A novel role of PRL in regulating epithelial cell density by inducing apoptosis at confluence. J Cell Sci 2021; 135:273809. [PMID: 34931244 DOI: 10.1242/jcs.258550] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 12/02/2021] [Indexed: 11/20/2022] Open
Abstract
Maintaining proper epithelial cell density is essential for the survival of multicellular organisms. While regulation of cell density through apoptosis is well known, its mechanistic details remain elusive. Here, we report the involvement of membrane-anchored phosphatase of regenerating liver (PRL), originally known for its role in cancer malignancy, in this process. In epithelial MDCK cells, upon confluence, doxycycline-induced expression of PRL upregulated apoptosis, reducing the cell density. This could be circumvented by artificially reducing the cell density via stretching the cell-seeded silicon chamber. Moreover, siRNA-mediated knockdown of endogenous PRL blocked apoptosis, leading to greater cell density. Mechanistically, PRL promoted apoptosis by upregulating the translation of E-cadherin and activating TGF-β pathway. Morpholino-mediated inhibition of PRL expression in zebrafish embryos caused developmental defect with reduced apoptosis and increased epithelial cell density during convergent extension. This study revealed a novel role of PRL in regulating density-dependent apoptosis in vertebrate epithelium.
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Affiliation(s)
- Sweksha Lohani
- Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yosuke Funato
- Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yuki Akieda
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
| | - Kiyohito Mizutani
- Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0047, Japan
| | - Yoshimi Takai
- Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0047, Japan
| | - Tohru Ishitani
- Department of Homeostatic Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.,Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka 565-0871, Japan
| | - Hiroaki Miki
- Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.,Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka 565-0871, Japan
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Rasool M, Malik A, Waquar S, Ain QT, Rasool R, Asif M, Anfinan N, Haque A, Alam H, Ahmed S, Hamid Hamdard M. Assessment of clinical variables as predictive markers in the development and progression of colorectal cancer. Bioengineered 2021; 12:2288-2298. [PMID: 34096454 PMCID: PMC8806642 DOI: 10.1080/21655979.2021.1933680] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is graded as one of the most common cancer. It accounts for the second leading cause of cancer deaths worldwide. The present study intends to investigate the role and importance of different biochemical variables in the development of colorectal cancer.In this cross-sectional study we recruited ninety-one patients diagnosed with colorectal cancer and fifty-three age-sex matched controls from June 2017 to June 2018. Different variables i.e. SOD, GSH, CAT, MDA, TGF, VEGF, TNF, ILs, MMPs, etc., were estimated with the help of their respective methods. Our findings suggest a significant increase in the levels of different inflammatory and stress-related markers. The NFκB, TGF-β, VEGFβ, 8OHdG, IsoP-2α were significantly found to be increased in patients with colon cancer (0.945 ± 0.067 μg/ml, 18.59 ± 1.53 pg/ml, 99.35 ± 4.29 pg/ml, 21.26 ± 1.29 pg/ml, 102.25 ± 4.25 pg/ml) as compared to controls (0.124 ± 0.024 μg/ml, 8.26 ± 0.88 pg/ml, 49.58 ± 2.62 pg/ml, 0.93 ± 0.29 pg/ml, 19.65 ± 3.19 pg/ml). Notably, the levels of different antioxidants were shown to be significantly lower in patients of colon cancer. The present study concluded that excessive oxidative stress and lipid peroxidation result in a decrease in the antioxidative capacity of cells which may influence diverse signaling cascades including NF-KB, which results in DNA modification and gene transcription that ultimately involved in the progression of colon cancer.
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Affiliation(s)
- Mahmood Rasool
- Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Arif Malik
- Institute of Molecular Biology and Biotechnology, the University of Lahore, Lahore, Pakistan
| | - Sulayman Waquar
- Institute of Molecular Biology and Biotechnology, the University of Lahore, Lahore, Pakistan
| | - Qura Tul Ain
- Institute of Molecular Biology and Biotechnology, the University of Lahore, Lahore, Pakistan
| | - Rabia Rasool
- Institute of Molecular Biology and Biotechnology, the University of Lahore, Lahore, Pakistan
| | - Muhammad Asif
- Department of Biotechnology, BUITEMS, Quetta, Pakistan
- ORIC, Buitems, Quetta, Pakistan
| | - Nisreen Anfinan
- Gynecology Oncology Unit, Obstetrics and Gynaecology Department, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
| | - Absarul Haque
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hina Alam
- Pakistan Institute of Medical Sciences, Islamabad, Pakistan
| | - Sagheer Ahmed
- Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University Islamabad
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Yu J, He Z, He X, Luo Z, Lian L, Wu B, Lan P, Chen H. Comprehensive Analysis of the Expression and Prognosis for MMPs in Human Colorectal Cancer. Front Oncol 2021; 11:771099. [PMID: 34804973 PMCID: PMC8602079 DOI: 10.3389/fonc.2021.771099] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 10/13/2021] [Indexed: 12/22/2022] Open
Abstract
Background Previous study implicated that genes of matrix metalloproteinase (MMP) family play an important role in tumor invasion, neoangiogenesis, and metastasis. However, the diverse expression patterns and prognostic values of 24 MMPs in colorectal cancer are yet to be analyzed. Methods In this study, by integrating public database and our data, we first investigated the expression levels and protein levels of MMPs in patients with colorectal cancer. Then, by using TCGA and GEO datasets, we evaluated the association of MMPs with clinicopathological parameters and prognosis of colorectal cancer. Finally, by using the cBioPortal online tool, we analyzed the alterations of MMPs and did the network and pathway analyses for MMPs and their nearby genes. Results We found that, MMP1, MMP3, MMP7, MMP9–MMP12, and MMP14 were consistently upregulated in public dataset and our samples. Whereas, MMP28 was consistently downregulated in public dataset and our samples. In the clinicopathological analyses, upregulated MMP11, MMP14, MMP16, MMP17, MMP19, and MMP23B were significantly associated with a higher tumor stage. In the survival analyses, upregulated MMP11, MMP14, MMP17, and MMP19 were significantly associated with a shorter progression-free survival (PFS) time and a shorter relapse-free (RFS) time. Discussion This study implied that MMP11, MMP14, MMP17, and MMP19 are potential targets of precision therapy for patients with colorectal cancer.
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Affiliation(s)
- Jing Yu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Zhen He
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Xiaowen He
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Zhanhao Luo
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Lei Lian
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Baixing Wu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for Ribose Nucleic Acid (RNA) Medicine, Ribose Nucleic Acid (RNA) Biomedical Institute, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ping Lan
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Haitao Chen
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China.,School of Public Health, Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
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30
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Rosic J, Dragicevic S, Miladinov M, Despotovic J, Bogdanovic A, Krivokapic Z, Nikolic A. SMAD7 and SMAD4 expression in colorectal cancer progression and therapy response. Exp Mol Pathol 2021; 123:104714. [PMID: 34717960 DOI: 10.1016/j.yexmp.2021.104714] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 08/12/2021] [Accepted: 10/18/2021] [Indexed: 12/24/2022]
Abstract
Inhibitory SMAD7 and common mediator SMAD4 play crucial roles in SMAD-dependent TGF-β signaling that is often disrupted in colorectal cancer (CRC). This study aimed to profile the expression of SMAD7 and SMAD4 in primary and metastatic CRC and to evaluate their significance in disease progression and therapy response. The expression of SMAD7 and SMAD4 genes was analyzed by quantitative real-time PCR in tissues from 35 primary and metastatic CRC patients and in vitro in 7 human cell lines originating from colon tissue. Expression levels of SMAD7 and SMAD4, as well as their ratio, were determined and their association with tumor characteristics and response to therapy were evaluated. SMAD4 level was significantly lower in tumors compared to non-tumor tissues in both primary (p = 0.001) and metastatic (p = 0.001) CRC patients, while tumor expression of SMAD7 was significantly lower from non-tumor tissue only in metastatic patients (p = 0.017). SMAD7/SMAD4 ratio was elevated in CRC primary tumor tissues and cell lines compared to corresponding non-tumor tissues and cell line, respectively (p = 0.003). SMAD7 expression was significantly elevated in primary tumor tissues obtained from responders to neoadjuvant chemoradiotherapy (nCRT) compared to non-responders (p = 0.014). Alterations of expression and ratio of SMAD7 and SMAD4 in CRC cell lines, primary rectal cancer, and liver metastasis emphasize the importance of these genes in different stages of disease progression. Differential expression of SMAD7 in responders versus non-responders to nCRT should be further investigated for its potential predictive value.
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Affiliation(s)
- Jovana Rosic
- School of Medicine, University of Belgrade, 11 000 Belgrade, Serbia.
| | - Sandra Dragicevic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11 000 Belgrade, Serbia
| | - Marko Miladinov
- Clinic for Digestive Surgery, University Clinical Center of Serbia, 11 000 Belgrade, Serbia
| | - Jovana Despotovic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11 000 Belgrade, Serbia
| | - Aleksandar Bogdanovic
- School of Medicine, University of Belgrade, 11 000 Belgrade, Serbia; Clinic for Digestive Surgery, University Clinical Center of Serbia, 11 000 Belgrade, Serbia
| | - Zoran Krivokapic
- School of Medicine, University of Belgrade, 11 000 Belgrade, Serbia; Clinic for Digestive Surgery, University Clinical Center of Serbia, 11 000 Belgrade, Serbia; Serbian Academy of Sciences and Arts, 11 000 Belgrade, Serbia
| | - Aleksandra Nikolic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11 000 Belgrade, Serbia
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31
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Sabbadini F, Bertolini M, De Matteis S, Mangiameli D, Contarelli S, Pietrobono S, Melisi D. The Multifaceted Role of TGF-β in Gastrointestinal Tumors. Cancers (Basel) 2021; 13:cancers13163960. [PMID: 34439114 PMCID: PMC8391793 DOI: 10.3390/cancers13163960] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/29/2021] [Accepted: 08/03/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary The transforming growth factor β signaling pathway elicits a broad range of physiological re-sponses, and its misregulation has been related to cancer. The secreted cytokine TGFβ exerts a tumor-suppressive effect that counteracts malignant transformation. However, once tumor has developed, TGFβ can support tumor progression regulating epithelial to mesenchymal transition, invasion and metastasis, stimulating fibrosis, angiogenesis and immune suppression. Here we review the dichotomous role of TGF-β in the progression of gastrointestinal tumors, as well as its intricate crosstalk with other signaling pathways. We also discuss about the therapeutic strate-gies that are currently explored in clinical trials to counteract TGF-β functions. Abstract Transforming growth factor-beta (TGF-β) is a secreted cytokine that signals via serine/threonine kinase receptors and SMAD effectors. Although TGF-β acts as a tumor suppressor during the early stages of tumorigenesis, it supports tumor progression in advanced stages. Indeed, TGF-β can modulate the tumor microenvironment by modifying the extracellular matrix and by sustaining a paracrine interaction between neighboring cells. Due to its critical role in cancer development and progression, a wide range of molecules targeting the TGF-β signaling pathway are currently under active clinical development in different diseases. Here, we focused on the role of TGF-β in modulating different pathological processes with a particular emphasis on gastrointestinal tumors.
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Affiliation(s)
- Fabio Sabbadini
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Monica Bertolini
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Serena De Matteis
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
- Department of Experimental, Diagnostic and Specialty Medicine, AlmaMater Studiorum, University of Bologna, 40126 Bologna, Italy
| | - Domenico Mangiameli
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Serena Contarelli
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Silvia Pietrobono
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
| | - Davide Melisi
- Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (F.S.); (M.B.); (S.D.M.); (D.M.); (S.C.); (S.P.)
- Experimental Cancer Medicine Unit, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy
- Correspondence:
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32
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Parajuli G, Tekguc M, Wing JB, Hashimoto A, Okuzaki D, Hirata T, Sasaki A, Itokazu T, Handa H, Sugino H, Nishikawa Y, Metwally H, Kodama Y, Tanaka S, Sabe H, Yamashita T, Sakaguchi S, Kishimoto T, Hashimoto S. Arid5a Promotes Immune Evasion by Augmenting Tryptophan Metabolism and Chemokine Expression. Cancer Immunol Res 2021; 9:862-876. [PMID: 34006522 DOI: 10.1158/2326-6066.cir-21-0014] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/05/2021] [Accepted: 05/14/2021] [Indexed: 11/16/2022]
Abstract
The acquisition of mesenchymal traits leads to immune evasion in various cancers, but the underlying molecular mechanisms remain unclear. In this study, we found that the expression levels of AT-rich interaction domain-containing protein 5a (Arid5a), an RNA-binding protein, were substantially increased in mesenchymal tumor subtypes. The deletion of Arid5a in tumor cell lines enhanced antitumor immunity in immunocompetent mice, but not in immunodeficient mice, suggesting a role for Arid5a in immune evasion. Furthermore, an Arid5a-deficient tumor microenvironment was shown to have robust antitumor immunity, as manifested by suppressed infiltration of granulocytic myeloid-derived suppressor cells and regulatory T cells. In addition, infiltrated T cells were more cytotoxic and less exhausted. Mechanistically, Arid5a stabilized Ido1 and Ccl2 mRNAs and augmented their expression, resulting in enhanced tryptophan catabolism and an immunosuppressive tumor microenvironment. Thus, our findings demonstrate the role of Arid5a beyond inflammatory diseases and suggest Arid5a as a promising target for the treatment of immunotolerant malignant tumors.See related Spotlight by Van den Eynde, p. 854.
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Affiliation(s)
- Gyanu Parajuli
- Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Murat Tekguc
- Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - James B Wing
- Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Ari Hashimoto
- Department of Molecular Biology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Daisuke Okuzaki
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Takeshi Hirata
- Department of Molecular Neuroscience, Graduate School of Medicine/Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.,Department of Neuro-Medical Science, Graduate School of Medicine, Osaka University, Osaka, Japan.,Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan
| | - Atsushi Sasaki
- Department of Molecular Neuroscience, Graduate School of Medicine/Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.,Department of Neuro-Medical Science, Graduate School of Medicine, Osaka University, Osaka, Japan.,Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan
| | - Takahide Itokazu
- Department of Molecular Neuroscience, Graduate School of Medicine/Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.,Department of Neuro-Medical Science, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Haruka Handa
- Department of Molecular Biology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Hirokazu Sugino
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Yoshihiro Nishikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hozaifa Metwally
- Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Yuzo Kodama
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan
| | - Shinya Tanaka
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan.,Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo, Japan
| | - Hisataka Sabe
- Department of Molecular Biology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Toshihide Yamashita
- Department of Molecular Neuroscience, Graduate School of Medicine/Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.,Department of Neuro-Medical Science, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Shimon Sakaguchi
- Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Tadamitsu Kishimoto
- Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
| | - Shigeru Hashimoto
- Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
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33
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Rasti A, Madjd Z, Saeednejad Zanjani L, Babashah S, Abolhasani M, Asgari M, Mehrazma M. SMAD4 Expression in Renal Cell Carcinomas Correlates With a Stem-Cell Phenotype and Poor Clinical Outcomes. Front Oncol 2021; 11:581172. [PMID: 34012911 PMCID: PMC8127783 DOI: 10.3389/fonc.2021.581172] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 03/18/2021] [Indexed: 01/17/2023] Open
Abstract
Renal cell carcinoma (RCC) is the most lethal neoplasm of common urologic cancers with poor prognoses. SMAD4 has a principal role in TGF-β (Transformis growth factorβ)-induced epithelial to mesenchymal transition (EMT) as a key factor in gaining cancer stem cell (CSC) features and tumor aggressiveness. This study aimed to evaluate the expression patterns and clinical significance of SMAD4 in RCC and the impact of its targeting on stem cell/mesenchymal cells and EMT characteristics in renal spheroid derived cells (SDCs) compared to parental cells (PCs) in RCC. The expression pattern and clinical significance of SMAD4 was evaluated in RCC. SDCs were enriched using a sphere culture system. Then SDCs and their PCs were compared with respect to their sphere and colony formation, expression of putative CSC markers, invasiveness as well as expression of genes, including stemness/mesenchymal, SMAD4 and TGFβ1genes. Finally, the effect of SMAD4 knockdown on SDCs was analyzed. We demonstrated that SMAD4 is positively correlated with decreased disease specific survival (DSS) in RCC patients and clear cell RCC (ccRCC) subtype and associates with poor DSS in patients with RCC, especially in ccRCC as the most metastatic RCC subtype. SDCs exhibited higher stem cell/mesenchymal properties. Inhibition of SMAD4 in PCs accelerated the dissociation of SDCs and decreased their clonogenicity, invasiveness, expression of mesenchymal markers and expression of SMAD4 and TGFβ1 genes compared to SDCs before transfection. We suggest that targeting SMAD4 may be useful against renal CSCs and may improve RCC prognosis.
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Affiliation(s)
- Arezoo Rasti
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.,Cellular and Molecular Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.,Department of Basic Sciences/Medical Surgical Nursing, Faculty of Nursing and Midwifery, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Zahra Madjd
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.,Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | | | - Sadegh Babashah
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University (TMU), Tehran, Iran
| | - Maryam Abolhasani
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.,Hasheminejad Kidney Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Mojgan Asgari
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.,Hasheminejad Kidney Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Mitra Mehrazma
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.,Hasheminejad Kidney Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
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34
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Zhang BH, Wang C, Dong W, Chen X, Leng C, Luo X, Dong SL, Yin P, Zhang BX, Datta PK, Chen XP. A novel approach for monitoring TGF-β signaling in vivo in colon cancer. Carcinogenesis 2021; 42:631-639. [PMID: 33367515 DOI: 10.1093/carcin/bgaa142] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 12/14/2020] [Accepted: 12/23/2020] [Indexed: 12/11/2022] Open
Abstract
The TGF-β receptor kinase inhibitors (TRKI) have been reported to inhibit tumorigenicity in colon cancer. However, there is no direct evidence showing that these inhibitors function through inhibiting the TGF-β- mediated tumor-promoting effects in vivo. We established a TGF-β inducible reporter system by inserting a luciferase reporter gene to the vector downstream of TGF-β-inducible promoter elements, and transfected it into colon cancer cell lines. TRKIs SB431542 and LY2109761 were used to treat TGF-β inducible cells in vitro and in vivo. The luciferase activity was induced 5.24-fold by TGF-β in CT26 inducible cells, while it was marginally changed in MC38 inducible cells lacking Smad4 expression. Temporary treatment of mice with SB431542 inhibited the TGF-β pathway and TGF-β induced bioluminescence activity in vivo. Long-term treatment with LY2109761 inhibited tumorigenicity and liver metastasis in vivo in concomitant with reduced luciferase activity in the tumor. In this study, we established a model to monitor the TGF-β pathway in vivo and to compare the antitumor effects of TRKIs. Based on this novel experimental tool, we provided direct evidences that LY2109761 inhibits tumorigenicity and liver metastasis by blocking the pro-oncogenic functions of TGF-β in vivo.
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Affiliation(s)
- Bin-Hao Zhang
- Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, China
| | - Chao Wang
- Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Dong
- Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Chen
- Department of Oncology, Tongji Hospital
| | - Chao Leng
- Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Luo
- Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Shui-Lin Dong
- Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Ping Yin
- Department of Epidemiology and Biostatistics School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bi-Xiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Pran K Datta
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
- Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
| | - Xiao-Ping Chen
- Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, China
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35
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Dos Santos IL, Penna KGBD, Dos Santos Carneiro MA, Libera LSD, Ramos JEP, Saddi VA. Tissue micro-RNAs associated with colorectal cancer prognosis: a systematic review. Mol Biol Rep 2021; 48:1853-1867. [PMID: 33598796 DOI: 10.1007/s11033-020-06075-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 12/10/2020] [Indexed: 01/05/2023]
Abstract
Colorectal cancer (CRC) is a multifactorial disease commonly diagnosed worldwide, with high mortality rates. Several studies demonstrate important associations between differential expression of micro-RNAs (miRs) and the prognosis of CRC. The present study aimed to identify differentially expressed tissue miRs associated with prognostic factors in CRC patients, through a systematic review of the Literature. Using the PubMed database, Cochrane Library and Web of Science, studies published in English evaluating miRs differentially expressed in tumor tissue and significantly associated with the prognostic aspects of CRC were selected. All the included studies used RT-PCR (Taqman or SYBR Green) for miR expression analysis and the period of publication was from 2009 to 2018. A total of 115 articles accomplished the inclusion criteria and were included in the review. The studies investigated the expression of 100 different miRs associated with prognostic aspects in colorectal cancer patients. The most frequent oncogenic miRs investigated were miR-21, miR-181a, miR-182, miR-183, miR-210 and miR-224 and the hyperexpression of these miRs was associated with distant metastasis, lymph node metastasis and worse survival in patients with CRC. The most frequent tumor suppressor miRs were miR-126, miR-199b and miR-22 and the hypoexpression of these miRs was associated with distant metastasis, worse prognosis and a higher risk of disease relapse (worse disease-free survival). Specific tissue miRs are shown to be promising prognostic biomarkers in patients with CRC, given their strong association with the prognostic aspects of these tumors, however, new studies are necessary to establish the sensibility and specificity of the individual miRs in order to use them in clinical practice.
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Affiliation(s)
- Igor Lopes Dos Santos
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil.
| | - Karlla Greick Batista Dias Penna
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
| | | | | | - Jéssica Enocencio Porto Ramos
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
| | - Vera Aparecida Saddi
- Programa de Mestrado em Ciências Ambientais e Saúde da Pontifícia Universidade Católica de Goiás, Laboratório de Genética e Biodiversidade, Escola de Ciências Médicas, Farmacêuticas e Biomédicas da Pontifícia Universidade Católica de Goiás, Área IV, Praça Universitária, 1440, Setor Leste Universitário, Goiânia, GO, 74605-010, Brazil
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36
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Hofving T, Elias E, Rehammar A, Inge L, Altiparmak G, Persson M, Kristiansson E, Johansson ME, Nilsson O, Arvidsson Y. SMAD4 haploinsufficiency in small intestinal neuroendocrine tumors. BMC Cancer 2021; 21:101. [PMID: 33509126 PMCID: PMC7841913 DOI: 10.1186/s12885-021-07786-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 01/02/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Patients with small intestinal neuroendocrine tumors (SINETs) frequently present with lymph node and liver metastases at the time of diagnosis, but the molecular changes that lead to the progression of these tumors are largely unknown. Sequencing studies have only identified recurrent point mutations at low frequencies with CDKN1B being the most common harboring heterozygous mutations in less than 10% of all tumors. Although SINETs are genetically stable tumors with a low frequency of point mutations and indels, they often harbor recurrent hemizygous copy number alterations (CNAs) yet the functional implications of these CNA are unclear. METHODS Utilizing comparative genomic hybridization (CGH) arrays we analyzed the CNA profile of 131 SINETs from 117 patients. Two tumor suppressor genes and corresponding proteins i.e. SMAD4, and CDKN1B, were further characterized using a tissue microarray (TMA) with 846 SINETs. Immunohistochemistry (IHC) was used to quantify protein expression in TMA samples and this was correlated with chromosome number evaluated with fluorescent in-situ hybridization (FISH). Intestinal tissue from a Smad4+/- mouse model was used to detect entero-endocrine cell hyperplasia with IHC. RESULTS Analyzing the CGH arrays we found loss of chromosome 18q and SMAD4 in 71% of SINETs and that focal loss of chromosome 12 affecting the CDKN1B was present in 9.4% of SINETs. No homozygous loss of chromosome 18 was detected. Hemizygous loss of SMAD4, but not CDKN1B, significantly correlated with reduced protein levels but hemizygous loss of SMAD4 did not induce entero-endocrine cell hyperplasia in the Smad4+/- mouse model. In addition, patients with low SMAD4 protein expression in primary tumors more often presented with metastatic disease. CONCLUSIONS Hemizygous loss of chromosome 18q and the SMAD4 gene is the most common genetic event in SINETs and our results suggests that this could influence SMAD4 protein expression and spread of metastases. Although SMAD4 haploinsufficiency alone did not induce tumor initiation, loss of chromosome 18 could represent an evolutionary advantage in SINETs explaining the high prevalence of this aberration. Functional consequences of reduced SMAD4 protein levels could hypothetically be a potential mechanism as to why loss of chromosome 18 appears to be clonally selected in SINETs.
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Affiliation(s)
- Tobias Hofving
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Box 425, SE-405 30, Gothenburg, Sweden
| | - Erik Elias
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Anna Rehammar
- Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden
| | - Linda Inge
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Box 425, SE-405 30, Gothenburg, Sweden
| | - Gülay Altiparmak
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Box 425, SE-405 30, Gothenburg, Sweden
| | - Marta Persson
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Box 425, SE-405 30, Gothenburg, Sweden
| | - Erik Kristiansson
- Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden
| | - Martin E Johansson
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Box 425, SE-405 30, Gothenburg, Sweden
| | - Ola Nilsson
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Box 425, SE-405 30, Gothenburg, Sweden
| | - Yvonne Arvidsson
- Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Box 425, SE-405 30, Gothenburg, Sweden.
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Chen J, Ding ZY, Li S, Liu S, Xiao C, Li Z, Zhang BX, Chen XP, Yang X. Targeting transforming growth factor-β signaling for enhanced cancer chemotherapy. Theranostics 2021; 11:1345-1363. [PMID: 33391538 PMCID: PMC7738904 DOI: 10.7150/thno.51383] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 10/29/2020] [Indexed: 12/14/2022] Open
Abstract
During the past decades, drugs targeting transforming growth factor-β (TGFβ) signaling have received tremendous attention for late-stage cancer treatment since TGFβ signaling has been recognized as a prime driver for tumor progression and metastasis. Nonetheless, in healthy and pre-malignant tissues, TGFβ functions as a potent tumor suppressor. Furthermore, TGFβ signaling plays a key role in normal development and homeostasis by regulating cell proliferation, differentiation, migration, apoptosis, and immune evasion, and by suppressing tumor-associated inflammation. Therefore, targeting TGFβ signaling for cancer therapy is challenging. Recently, we and others showed that blocking TGFβ signaling increased chemotherapy efficacy, particularly for nanomedicines. In this review, we briefly introduce the TGFβ signaling pathway, and the multifaceted functions of TGFβ signaling in cancer, including regulating the tumor microenvironment (TME) and the behavior of cancer cells. We also summarize TGFβ targeting agents. Then, we highlight TGFβ inhibition strategies to restore the extracellular matrix (ECM), regulate the tumor vasculature, reverse epithelial-mesenchymal transition (EMT), and impair the stemness of cancer stem-like cells (CSCs) to enhance cancer chemotherapy efficacy. Finally, the current challenges and future opportunities in targeting TGFβ signaling for cancer therapy are discussed.
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Affiliation(s)
- Jitang Chen
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Ze-yang Ding
- Hepatic Surgery Center, and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, National Medical Center for Major Public Health Events, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Si Li
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Sha Liu
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
- Hepatic Surgery Center, and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, National Medical Center for Major Public Health Events, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chen Xiao
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Zifu Li
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Bi-xiang Zhang
- Hepatic Surgery Center, and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, National Medical Center for Major Public Health Events, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao-ping Chen
- Hepatic Surgery Center, and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, National Medical Center for Major Public Health Events, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangliang Yang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan, 430074, China
- GBA Research Innovation Institute for Nanotechnology, Guangdong, 510530, China
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Schwarzmueller L, Bril O, Vermeulen L, Léveillé N. Emerging Role and Therapeutic Potential of lncRNAs in Colorectal Cancer. Cancers (Basel) 2020; 12:E3843. [PMID: 33352769 PMCID: PMC7767007 DOI: 10.3390/cancers12123843] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 02/06/2023] Open
Abstract
Maintenance of the intestinal epithelium is dependent on the control of stem cell (SC) proliferation and differentiation. The fine regulation of these cellular processes requires a complex dynamic interplay between several signaling pathways, including Wnt, Notch, Hippo, EGF, Ephrin, and BMP/TGF-β. During the initiation and progression of colorectal cancer (CRC), key events, such as oncogenic mutations, influence these signaling pathways, and tilt the homeostatic balance towards proliferation and dedifferentiation. Therapeutic strategies to specifically target these deregulated signaling pathways are of particular interest. However, systemic blocking or activation of these pathways poses major risks for normal stem cell function and tissue homeostasis. Interestingly, long non-coding RNAs (lncRNAs) have recently emerged as potent regulators of key cellular processes often deregulated in cancer. Because of their exceptional tissue and tumor specificity, these regulatory RNAs represent attractive targets for cancer therapy. Here, we discuss how lncRNAs participate in the maintenance of intestinal homeostasis and how they can contribute to the deregulation of each signaling pathway in CRC. Finally, we describe currently available molecular tools to develop lncRNA-targeted cancer therapies.
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Affiliation(s)
- Laura Schwarzmueller
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.S.); (O.B.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Oscar Bril
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.S.); (O.B.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Louis Vermeulen
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.S.); (O.B.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Nicolas Léveillé
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.S.); (O.B.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
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Marvin DL, Heijboer R, ten Dijke P, Ritsma L. TGF-β signaling in liver metastasis. Clin Transl Med 2020; 10:e160. [PMID: 33252863 PMCID: PMC7701955 DOI: 10.1002/ctm2.160] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/07/2020] [Accepted: 08/11/2020] [Indexed: 12/12/2022] Open
Abstract
The presence of liver metastases drastically worsens the prognosis of cancer patients. The liver is the second most prevalent metastatic site in cancer patients, but systemic therapeutic opportunities that target liver metastases are still limited. To aid the discovery of novel treatment options for metastatic liver disease, we provide insight into the cellular and molecular steps required for liver colonization. For successful colonization in the liver, adaptation of tumor cells and surrounding stroma is essential. This includes the formation of a pre-metastatic niche, the creation of a fibrotic and immune suppressive environment, angiogenesis, and adaptation of tumor cells. We illustrate that transforming growth factor β (TGF-β) is a central cytokine in all these processes. At last, we devise that future research should focus on TGF-β inhibitory strategies, especially in combination with immunotherapy. This promising systemic treatment strategy has potential to eliminate distant metastases as the efficacy of immunotherapy will be enhanced.
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Affiliation(s)
- Dieuwke L Marvin
- Department of Cell and Chemical Biology and Oncode InstituteLeiden University Medical CenterLeidenThe Netherlands
| | - Rosan Heijboer
- Department of Cell and Chemical Biology and Oncode InstituteLeiden University Medical CenterLeidenThe Netherlands
| | - Peter ten Dijke
- Department of Cell and Chemical Biology and Oncode InstituteLeiden University Medical CenterLeidenThe Netherlands
| | - Laila Ritsma
- Department of Cell and Chemical Biology and Oncode InstituteLeiden University Medical CenterLeidenThe Netherlands
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Quigley NG, Steiger K, Richter F, Weichert W, Hoberück S, Kotzerke J, Notni J. Tracking a TGF-β activator in vivo: sensitive PET imaging of αvβ8-integrin with the Ga-68-labeled cyclic RGD octapeptide trimer Ga-68-Triveoctin. EJNMMI Res 2020; 10:133. [PMID: 33128636 PMCID: PMC7603442 DOI: 10.1186/s13550-020-00706-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 09/21/2020] [Indexed: 01/02/2023] Open
Abstract
Purpose As a major activator of transforming growth factor β (TGF-β), the RGD receptor αvβ8-integrin is involved in pathogenic processes related to TGF-β dysregulation, such as tumor growth, invasion, and radiochemoresistance, metastasis and tumor cell stemness, as well as epithelial-mesenchymal transition. The novel positron emission tomography (PET) radiopharmaceutical Ga-68-Triveoctin for in vivo mapping of αvβ8-integrin expression might enhance the prognosis of certain tumor entities, as well as support and augment TGF-β-targeted therapeutic approaches. Methods Monomeric and trimeric conjugates of cyclo(GLRGDLp(NMe)K(pent-4-ynoic amide)) were synthesized by click chemistry (CuAAC), labeled with Ga-68, and evaluated in MeWo (human melanoma) xenografted SCID mice by means of PET and ex-vivo biodistribution. αvβ8-integrin expression in murine tissues was determined by β8-IHC. A human subject received a single injection of 173 MBq of Ga-68-Triveoctin and underwent 3 subsequent PET/CT scans at 25, 45, and 90 min p.i.. Results The trimer Ga-68-Triveoctin exhibits a 6.7-fold higher αvβ8-integrin affinity than the monomer (IC50 of 5.7 vs. 38 nM, respectively). Accordingly, biodistribution showed a higher tumor uptake (1.9 vs. 1.0%IA/g, respectively) but a similar baseline upon blockade (0.25%IA/g for both). IHC showed an intermediate β8-expression in the tumor while most organs and tissues were found β8-negative. Low non-target tissue uptakes (< 0.4%IA/g) confirmed a low degree of unspecific binding. Due to its hydrophilicity (log D = − 3.1), Ga-68-Triveoctin is excreted renally and shows favorable tumor/tissue ratios in mice (t/blood: 6.7; t/liver: 6.8; t/muscle: 29). A high kidney uptake in mice (kidney-to-blood and -to-muscle ratios of 126 and 505, respectively) is not reflected by human PET (corresponding values are 15 and 30, respectively), which furthermore showed notable uptakes in coeliac and choroid plexus (SUVmean 6.1 and 9.7, respectively, 90 min p.i.). Conclusion Ga-68-Triveoctin enables sensitive in-vivo imaging αvβ8-integrin expression in murine tumor xenografts. PET in a human subject confirmed a favorable biodistribution, underscoring the potential of Ga-68-Triveoctin for mapping of αvβ8-integrin expression in a clinical setting.
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Affiliation(s)
- Neil Gerard Quigley
- Institut für Pathologie Und Pathologische Anatomie, Technische Universität München, Trogerstraße 18, 81675, Munich, Germany
| | - Katja Steiger
- Institut für Pathologie Und Pathologische Anatomie, Technische Universität München, Trogerstraße 18, 81675, Munich, Germany
| | - Frauke Richter
- Institut für Pathologie Und Pathologische Anatomie, Technische Universität München, Trogerstraße 18, 81675, Munich, Germany
| | - Wilko Weichert
- Institut für Pathologie Und Pathologische Anatomie, Technische Universität München, Trogerstraße 18, 81675, Munich, Germany
| | - Sebastian Hoberück
- Klinik Und Poliklinik für Nuklearmedizin, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Germany
| | - Jörg Kotzerke
- Klinik Und Poliklinik für Nuklearmedizin, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Germany
| | - Johannes Notni
- Institut für Pathologie Und Pathologische Anatomie, Technische Universität München, Trogerstraße 18, 81675, Munich, Germany.
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Quigley NG, Tomassi S, di Leva FS, Di Maro S, Richter F, Steiger K, Kossatz S, Marinelli L, Notni J. Click-Chemistry (CuAAC) Trimerization of an α v β 6 Integrin Targeting Ga-68-Peptide: Enhanced Contrast for in-Vivo PET Imaging of Human Lung Adenocarcinoma Xenografts. Chembiochem 2020; 21:2836-2843. [PMID: 32359011 PMCID: PMC7586803 DOI: 10.1002/cbic.202000200] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/30/2020] [Indexed: 12/21/2022]
Abstract
αv β6 Integrin is an epithelial transmembrane protein that recognizes latency-associated peptide (LAP) and primarily activates transforming growth factor beta (TGF-β). It is overexpressed in carcinomas (most notably, pancreatic) and other conditions associated with αv β6 integrin-dependent TGF-β dysregulation, such as fibrosis. We have designed a trimeric Ga-68-labeled TRAP conjugate of the αv β6 -specific cyclic pentapeptide SDM17 (cyclo[RGD-Chg-E]-CONH2 ) to enhance αv β6 integrin affinity as well as target-specific in-vivo uptake. Ga-68-TRAP(SDM17)3 showed a 28-fold higher αv β6 affinity than the corresponding monomer Ga-68-NOTA-SDM17 (IC50 of 0.26 vs. 7.4 nM, respectively), a 13-fold higher IC50 -based selectivity over the related integrin αv β8 (factors of 662 vs. 49), and a threefold higher tumor uptake (2.1 vs. 0.66 %ID/g) in biodistribution experiments with H2009 tumor-bearing SCID mice. The remarkably high tumor/organ ratios (tumor-to-blood 11.2; -to-liver 8.7; -to-pancreas 29.7) enabled high-contrast tumor delineation in PET images. We conclude that Ga-68-TRAP(SDM17)3 holds promise for improved clinical PET diagnostics of carcinomas and fibrosis.
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Affiliation(s)
- Neil Gerard Quigley
- Institute of PathologyTechnische Universität MünchenTrogerstrasse 1881675MünchenGermany
| | - Stefano Tomassi
- Dipartimento di FarmaciaUniversità degli Studi di Napoli Federico IIVia D. Montesano 4980131NapoliItaly
| | - Francesco Saverio di Leva
- Dipartimento di FarmaciaUniversità degli Studi di Napoli Federico IIVia D. Montesano 4980131NapoliItaly
| | - Salvatore Di Maro
- Dipartimento di Scienze e Tecnologie Ambientali Biologiche e FarmaceuticheUniversità degli Studi della Campania “Luigi Vanvitelli”Via A. Vivaldi 4381100CasertaItaly
| | - Frauke Richter
- Institute of PathologyTechnische Universität MünchenTrogerstrasse 1881675MünchenGermany
| | - Katja Steiger
- Institute of PathologyTechnische Universität MünchenTrogerstrasse 1881675MünchenGermany
| | - Susanne Kossatz
- Klinik für Nuklearmedizin and TranslaTUMCentral Institute for Translational Cancer ResearchTechnische Universität MünchenIsmaninger Str. 2281675MünchenGermany
| | - Luciana Marinelli
- Dipartimento di FarmaciaUniversità degli Studi di Napoli Federico IIVia D. Montesano 4980131NapoliItaly
| | - Johannes Notni
- Institute of PathologyTechnische Universität MünchenTrogerstrasse 1881675MünchenGermany
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Cheung P, Xiol J, Dill MT, Yuan WC, Panero R, Roper J, Osorio FG, Maglic D, Li Q, Gurung B, Calogero RA, Yilmaz ÖH, Mao J, Camargo FD. Regenerative Reprogramming of the Intestinal Stem Cell State via Hippo Signaling Suppresses Metastatic Colorectal Cancer. Cell Stem Cell 2020; 27:590-604.e9. [PMID: 32730753 PMCID: PMC10114498 DOI: 10.1016/j.stem.2020.07.003] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 04/01/2020] [Accepted: 07/01/2020] [Indexed: 12/13/2022]
Abstract
Although the Hippo transcriptional coactivator YAP is considered oncogenic in many tissues, its roles in intestinal homeostasis and colorectal cancer (CRC) remain controversial. Here, we demonstrate that the Hippo kinases LATS1/2 and MST1/2, which inhibit YAP activity, are required for maintaining Wnt signaling and canonical stem cell function. Hippo inhibition induces a distinct epithelial cell state marked by low Wnt signaling, a wound-healing response, and transcription factor Klf6 expression. Notably, loss of LATS1/2 or overexpression of YAP is sufficient to reprogram Lgr5+ cancer stem cells to this state and thereby suppress tumor growth in organoids, patient-derived xenografts, and mouse models of primary and metastatic CRC. Finally, we demonstrate that genetic deletion of YAP and its paralog TAZ promotes the growth of these tumors. Collectively, our results establish the role of YAP as a tumor suppressor in the adult colon and implicate Hippo kinases as therapeutic vulnerabilities in colorectal malignancies.
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Affiliation(s)
- Priscilla Cheung
- Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Jordi Xiol
- Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Michael T Dill
- Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Wei-Chien Yuan
- Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Riccardo Panero
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy
| | - Jatin Roper
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA
| | - Fernando G Osorio
- Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Dejan Maglic
- Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Qi Li
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Basanta Gurung
- Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Raffaele A Calogero
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy
| | - Ömer H Yilmaz
- Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Junhao Mao
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Fernando D Camargo
- Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
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Liao Z, Chen L, Zhang X, Zhang H, Tan X, Dong K, Lu X, Zhu H, Liu Q, Zhang Z, Ding Z, Dong W, Zhu P, Chu L, Liang H, Datta PK, Zhang B, Chen X. PTPRε Acts as a Metastatic Promoter in Hepatocellular Carcinoma by Facilitating Recruitment of SMAD3 to TGF-β Receptor 1. Hepatology 2020; 72:997-1012. [PMID: 31903610 DOI: 10.1002/hep.31104] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 12/17/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Transforming growth factor beta (TGF-β) suppresses early stages of tumorigenesis, but contributes to the migration and metastasis of cancer cells. However, the role of TGF-β signaling in invasive prometastatic hepatocellular carcinoma (HCC) is poorly understood. In this study, we investigated the roles of canonical TGF-β/mothers against decapentaplegic homolog 3 (SMAD3) signaling and identified downstream effectors on HCC migration and metastasis. APPROACH AND RESULTS By using in vitro trans-well migration and invasion assays and in vivo metastasis models, we demonstrated that SMAD3 and protein tyrosine phosphatase receptor epsilon (PTPRε) promote migration, invasion, and metastasis of HCC cells in vitro and in vivo. Further mechanistic studies revealed that, following TGF-β stimulation, SMAD3 binds directly to PTPRε promoters to activate its expression. PTPRε interacts with TGFBR1/SMAD3 and facilitates recruitment of SMAD3 to TGFBR1, resulting in a sustained SMAD3 activation status. The tyrosine phosphatase activity of PTPRε is important for binding with TGFBR1, recruitment and activation of SMAD3, and its prometastatic role in vitro. A positive correlation between pSMAD3/SMAD3 and PTPRε expression was determined in HCC samples, and high expression of SMAD3 or PTPRε was associated with poor prognosis of patients with HCC. CONCLUSIONS PTPRε positive feedback regulates TGF-β/SMAD3 signaling to promote HCC metastasis.
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Affiliation(s)
- Zhibin Liao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Lin Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Xuewu Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Hongwei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Xiaolong Tan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Keshuai Dong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Xun Lu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - He Zhu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Qiumeng Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Zeyang Ding
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Wei Dong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Peng Zhu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Liang Chu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Pran K Datta
- Division of Hematology and Oncology, Department of Medicine, UAB Comprehensive Cancer Center, Birmingham, AL
- Birmingham Veterans Affairs Medical Center, Birmingham, AL
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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Vu T, Yang S, Datta PK. MiR-216b/Smad3/BCL-2 Axis Is Involved in Smoking-Mediated Drug Resistance in Non-Small Cell Lung Cancer. Cancers (Basel) 2020; 12:E1879. [PMID: 32668597 PMCID: PMC7408725 DOI: 10.3390/cancers12071879] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 07/09/2020] [Accepted: 07/10/2020] [Indexed: 12/12/2022] Open
Abstract
Epidemiologic studies have shown that vast majority of lung cancers (85-90%) are causally linked to tobacco smoking. Although much information has been gained about the effects of smoking on various signaling pathways, little is known about how deregulation of miRNAs leads to activation of oncogenes and inhibition of tumor suppressor genes in non-small cell lung cancer (NSCLC). Our previous study showed that smoking inhibits TGF-β-induced tumor suppressor functions through downregulation of Smad3 in lung cancer cells. In order to understand the upstream mechanism of downregulation of Smad3 by smoking, we performed miRNA microarray analyses after treating human lung adenocarcinoma A549 and immortalized peripheral lung epithelial HPL1A cells with cigarette smoke condensate (CSC). We identified miR-216b as being upregulated in CSC treated cells. MiR-216b overexpression decreases Smad3 protein expression by binding to its 3'-UTR, and attenuates transforming growth factor beta (TGF-β) signaling and target gene expression. MiR-216b increases B-cell lymphoma 2 (BCL-2) expression and promotes chemoresistance of NSCLC cells by decreasing apoptosis. Increased acetylation of histones H3 and H4 in miR-216b gene promoter plays a role in CSC induced miR-216b expression. Taken together, these results suggest that smoking-mediated upregulation of miR-216b increases NSCLC cell growth by downregulating Smad3 and inhibiting TGF-β-induced tumor suppressor function, and induces resistance to platinum-based therapy.
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Affiliation(s)
- Trung Vu
- Division of Hematology and Oncology, Department of Medicine, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.V.); (S.Y.)
- Birmingham Veterans Affairs Medical Center, Birmingham, AL 35233, USA
| | - Shanzhong Yang
- Division of Hematology and Oncology, Department of Medicine, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.V.); (S.Y.)
| | - Pran K. Datta
- Division of Hematology and Oncology, Department of Medicine, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (T.V.); (S.Y.)
- Birmingham Veterans Affairs Medical Center, Birmingham, AL 35233, USA
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Park S, Hong Y, Lee S, Lee AY, Tran Q, Lee H, Kim M, Park J, Cho MH, Park J. FCHO1 560-571 peptide, a PKB kinase motif, inhibits tumor progression. Biochem Biophys Res Commun 2020; 528:478-484. [PMID: 32507602 DOI: 10.1016/j.bbrc.2020.05.173] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 05/24/2020] [Indexed: 10/24/2022]
Abstract
BACKGROUND Cell division is regulated by protein kinase B (PKB)-mediated FCH domain only 1 (FCHO1) phosphorylation. METHODS FCHO1560-571, a synthetic water-soluble peptide, was generated from the PKB substrate motif 560PPRRLRSRKVSC571 found in the human FCHO1 protein. RESULTS In this study, we found that in vitro FCHO1560-571 inhibits cell proliferation via PKB/ERK/SMAD4 pathways in KRAS-mutated A549 lung cancer cells. In addition, FCHO1560-571, at effective doses of 15 and 30 mg/kg, significantly suppressed tumor growth and decreased the size and weight of tumors in A549-xenograft mice. CONCLUSION These results suggest that the FCHO1560-571 peptide could be a potential therapy for lung cancer.
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Affiliation(s)
- Sungjin Park
- Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI, 53706, USA; Department of Pharmacology, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015, South Korea
| | - Youngeun Hong
- Department of Pharmacology, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015, South Korea; Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, South Korea
| | - Soomin Lee
- Laboratory of Toxicology, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea
| | - Ah Young Lee
- Laboratory of Toxicology, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea
| | - Quangdon Tran
- Department of Pharmacology, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015, South Korea; Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, South Korea
| | - Hyunji Lee
- Department of Pharmacology, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015, South Korea; Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, South Korea
| | - Minhee Kim
- Department of Pharmacology, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015, South Korea; Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, South Korea
| | - Jisoo Park
- Department of Pharmacology, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015, South Korea; Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, South Korea; Department of Life Science, Hyehwa Liberal Arts College, Daejeon University, Daejeon, 34520, South Korea
| | - Myung-Haing Cho
- Laboratory of Toxicology, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.
| | - Jongsun Park
- Department of Pharmacology, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015, South Korea; Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, South Korea.
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Liao B, Sun Q, Yuan Y, Yin Y, Qiao J, Jiang P. Histone deacetylase inhibitor MGCD0103 causes cell cycle arrest, apoptosis, and autophagy in liver cancer cells. J Cancer 2020; 11:1915-1926. [PMID: 32194803 PMCID: PMC7052879 DOI: 10.7150/jca.34091] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 12/01/2019] [Indexed: 12/20/2022] Open
Abstract
Background: Liver cancer is a common cause of cancer-related death all over the world. MGCD0103, a histone deacetylase inhibitor, exerts antitumor effect on various cancers. However, its role in liver cancer remains unclear. Methods: The effect of MGCD0103 on HepG2 and Huh7 cells was verified by several experiments such as cell viability assay, colony formation assay, cell cycle analysis, apoptosis analysis, reactive oxygen species (ROS) assay, western blotting, immunohistochemistry, and xenograft assay. Results: Cell viability and colony formation assays showed that MGCD0103 inhibited the proliferation of liver cancer cells in vitro. Flow cytometry and western blotting analysis demonstrated that MGCD0103 induced G2/M phase arrest and mitochondrial-related apoptosis. A pan-caspase inhibitor and ROS scavenger inhibited apoptosis induced by MGCD0103. What's more, MGCD0103 led to autophagy associated with cell death and an autophagy inhibitor inhibited apoptosis and autophagy induced by MGCD0103. Ultimately, MGCD0103 attenuated tumor growth but did not show significant systemic toxicity in animal model. Conclusions: MGCD0103 suppressed the growth of liver cancer cells in vitro and in vivo. It could serve as a novel therapeutic approach for liver cancer.
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Affiliation(s)
- Bo Liao
- Department of Hepatopancreatobiliary Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Quan Sun
- Department of Hepatopancreatobiliary Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Yufeng Yuan
- Department of Hepatopancreatobiliary Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Yuchun Yin
- Department of Hepatopancreatobiliary Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Jianguo Qiao
- Department of Hepatopancreatobiliary Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Ping Jiang
- Department of Hepatopancreatobiliary Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
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Abstract
Transforming growth factor-beta (TGF-β) signaling is one of the important cellular pathways that play key roles for tissue maintenance. In particular, it is important in the context of inflammation and tumorigenesis by modulating cell growth, differentiation, apoptosis, and homeostasis. TGF-β receptor type 2 (TGFBR2) mutations affected by a mismatch repair deficiency causes colorectal cancers (CRCs) with microsatellite instability, which is, however, associated with relatively better survival rates. On the other hand, loss of SMAD4, a transcription factor in the TGF-β superfamily signaling, promotes tumor progression. Loss of heterozygosity on chromosome 18 can case SMAD4-deficient CRC, which results in poorer patients' survival. Such bidirectional phenomenon driven by TGF-β signaling insufficiency reflects the complexity of this signaling pathway in CRC. Moreover, recent understanding of CRC at the molecular level (consensus molecular subtype classification) provides deep insight into the important roles of TGF-β signaling in the tumor microenvironment. Here we focus on the TGF-β signaling in CRC and its interaction with the tumor microenvironment. We summarize the molecular mechanisms of CRC tumorigenesis and progression caused by disruption of TGF-β signaling by cancer epithelial cells and host stromal cells.
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Transforming Growth Factor-β Signaling Pathway in Colorectal Cancer and Its Tumor Microenvironment. Int J Mol Sci 2019; 20:ijms20235822. [PMID: 31756952 PMCID: PMC6929101 DOI: 10.3390/ijms20235822] [Citation(s) in RCA: 170] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Revised: 11/14/2019] [Accepted: 11/18/2019] [Indexed: 02/08/2023] Open
Abstract
Transforming growth factor-beta (TGF-β) signaling is one of the important cellular pathways that play key roles for tissue maintenance. In particular, it is important in the context of inflammation and tumorigenesis by modulating cell growth, differentiation, apoptosis, and homeostasis. TGF-β receptor type 2 (TGFBR2) mutations affected by a mismatch repair deficiency causes colorectal cancers (CRCs) with microsatellite instability, which is, however, associated with relatively better survival rates. On the other hand, loss of SMAD4, a transcription factor in the TGF-β superfamily signaling, promotes tumor progression. Loss of heterozygosity on chromosome 18 can case SMAD4-deficient CRC, which results in poorer patients’ survival. Such bidirectional phenomenon driven by TGF-β signaling insufficiency reflects the complexity of this signaling pathway in CRC. Moreover, recent understanding of CRC at the molecular level (consensus molecular subtype classification) provides deep insight into the important roles of TGF-β signaling in the tumor microenvironment. Here we focus on the TGF-β signaling in CRC and its interaction with the tumor microenvironment. We summarize the molecular mechanisms of CRC tumorigenesis and progression caused by disruption of TGF-β signaling by cancer epithelial cells and host stromal cells.
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Li X, Lv X, Li Z, Li C, Li X, Xiao J, Liu B, Yang H, Zhang Y. Long Noncoding RNA ASLNC07322 Functions in VEGF-C Expression Regulated by Smad4 during Colon Cancer Metastasis. MOLECULAR THERAPY. NUCLEIC ACIDS 2019; 18:851-862. [PMID: 31739210 PMCID: PMC6861657 DOI: 10.1016/j.omtn.2019.10.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 09/22/2019] [Accepted: 10/12/2019] [Indexed: 12/15/2022]
Abstract
Deletion and mutation of the Smad4 gene are favorable events for the progression of colon cancer, which is related to the negative regulation of vascular endothelial growth factor C (VEGF-C). However, the regulatory mechanism between Smad4 and VEGF-C remains unclear. We reported first that Smad4 can increase the transcription of miR-128-3p, a microRNA targeting VEGF-C mRNA, resulting in a negative correlation between Smad4 and VEGF-C. Moreover, we found that Smad4 combined with Smad3 can positively regulate VEGF-C during colon cancer metastasis through binding to VEGF-C gene promoter. Further, results revealed a mechanism that long noncoding RNA (lncRNA) ASLNC07322 increased specifically in metastatic colon cancer and decreased miR-128-3p as a sponge, leading to a subsequent elevation of VEGF-C. In a word, there are two pathways in the progression of colon cancer, including Smad4/miR-128-3p/VEGF-C and Smad4/VEGF-C pathways in non-metastatic and metastatic colon cancer, respectively. ASLNC07322 crucially controlled this negative and positive regulatory transformation between them. Additionally, ASLNC07322 knockdown combined with Smad4 overexpression could efficiently inhibit lymphatic endothelial cells (LECs) proliferation and tube formation in vitro, as well as tumor growth and lymphangiogenesis in vivo. These data explained the underlying mechanism of Smad4 contribution on VEGF-C expression during metastasis where ASLNC07322 functions vitally as a switch in colon cancer.
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Affiliation(s)
- Xuemei Li
- Department of Anatomy, Harbin Medical University, 157 Baojian Road, Harbin, China
| | - Xiaohong Lv
- Department of Anatomy, Harbin Medical University, 157 Baojian Road, Harbin, China
| | - Zhuowei Li
- Department of Anatomy, Harbin Medical University, 157 Baojian Road, Harbin, China
| | - Chao Li
- Department of Anatomy, Harbin Medical University, 157 Baojian Road, Harbin, China
| | - Xinlei Li
- Department of Anatomy, Harbin Medical University, 157 Baojian Road, Harbin, China
| | - Jianbing Xiao
- Department of Anatomy, Harbin Medical University, 157 Baojian Road, Harbin, China
| | - Baoquan Liu
- Department of Anatomy, Harbin Medical University, 157 Baojian Road, Harbin, China
| | - Huike Yang
- Department of Anatomy, Harbin Medical University, 157 Baojian Road, Harbin, China.
| | - Yafang Zhang
- Department of Anatomy, Harbin Medical University, 157 Baojian Road, Harbin, China.
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Zhu SM, Park YR, Seo SY, Kim IH, Lee ST, Kim SW. Parthenolide inhibits transforming growth factor β1-induced epithelial-mesenchymal transition in colorectal cancer cells. Intest Res 2019; 17:527-536. [PMID: 31426622 PMCID: PMC6821947 DOI: 10.5217/ir.2019.00031] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 05/28/2019] [Accepted: 06/07/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIMS Transforming growth factor-β1 (TGF-β1) induction of epithelial-mesenchymal transition (EMT) is one of the mechanisms by which colorectal cancer (CRC) cells acquire migratory and invasive capacities, and subsequently metastasize. Parthenolide (PT) expresses multiple anti-cancer and anti-inflammatory activities that inhibit nuclear factor κB by targeting the IκB kinase complex. In the present study, we aimed to investigate whether PT can inhibit TGF-β1-induced EMT in CRC cell lines. METHODS HT-29 and SW480 cell lines were used in the experiment. Cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and sub-G1 analysis was measured by flow cytometry. The induction of EMT by TGF-β1 and inhibition of the process by PT was analyzed by phase contrast microscopy, wounding healing, cellular migration and invasion assays, and Western blotting. RESULTS TGF-β1 inhibits HT-29 cell proliferation, but has no effect on SW480 cell proliferation; different concentrations of TGF-β1 did not induce apoptosis in HT-29 and SW480 cells. PT attenuates TGF-β1-induced elongated, fibroblast-like shape changing in cells. PT inhibits TGF-β1-induced cell migration and cell invasion. In addition, other EMT markers such as β-catenin, Vimentin, Snail, and Slug were suppressed by PT, while E-cadherin was increased by PT. CONCLUSIONS Our findings show that PT inhibits TGF-β1-induced EMT by suppressing the expression of the mesenchymal protein and increasing expression of the epithelial protein. These findings suggest a novel approach for CRC treatment by suppression of TGF-β1-induced EMT.
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Affiliation(s)
- Shi Mao Zhu
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University, and Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Yong Ran Park
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University, and Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Seung Yong Seo
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University, and Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - In Hee Kim
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University, and Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Soo Teik Lee
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University, and Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Sang Wook Kim
- Department of Internal Medicine, Research Institute of Clinical Medicine of Chonbuk National University, and Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
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