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1
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Shah H, Hill TA, Lim J, Fairlie DP. Protease-activated receptor 2 attenuates doxorubicin-induced apoptosis in colon cancer cells. J Cell Commun Signal 2023:10.1007/s12079-023-00791-6. [PMID: 37991681 DOI: 10.1007/s12079-023-00791-6] [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: 01/31/2023] [Accepted: 11/02/2023] [Indexed: 11/23/2023] Open
Abstract
Drug resistance represents a major problem in cancer treatment. Doxorubicin (adriamycin) is an injectable DNA intercalating drug that halts cancer cell growth by inhibiting topoisomerase 2, but its long-term effectiveness is compromised by onset of resistance. This study demonstrates that expression of the PAR2 gene in human colon adenocarcinoma tissue samples was the highest among 32 different cancer types (n = 10,989), and higher in colon adenocarcinoma tissues (n = 331) than normal colon tissues (n = 308), revealing an association between PAR2 expression and human colon cancer. HT29 cells are a human colorectal adenocarcinoma cell line that is sensitive to the chemotherapeutic drug doxorubicin and also expresses PAR2. We find that PAR2 activation in HT29 cells, either by an endogenous protease agonist (trypsin) or an exogenous peptide agonist (2f-LIGRL-NH2), significantly reduces doxorubicin-induced cell death, reactive oxygen species production, caspase 3/7 activity and cleavage of caspase-8 and caspase-3. Moreover, PAR2-mediated MEK1/2-ERK1/2 pathway induced by 2f-LIGRL-NH2 leads to upregulated anti-apoptotic MCL-1 and Bcl-xL proteins that promote cellular survival. These findings suggest that activation of PAR2 compromises efficacy of doxorubicin in colon cancer. Further support for this conclusion came from experiments with human colon cancer HT29 cells, either with the PAR2 gene deleted or in the presence of a pharmacological antagonist of PAR2, which showed full restoration of all doxorubicin-mediated effects. Together, these findings reveal a strong link between PAR2 activation and signalling in human colon cancer cells and increased survival against doxorubicin-induced cell death. They support PAR2 antagonism as a possible new strategy for enhancing doxorubicin therapy.
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Affiliation(s)
- Himani Shah
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia
- Centre for Chemistry and Drug Discovery, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia
| | - Timothy A Hill
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia
- Centre for Chemistry and Drug Discovery, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia
| | - Junxian Lim
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia.
- Centre for Chemistry and Drug Discovery, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia.
| | - David P Fairlie
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia.
- Centre for Chemistry and Drug Discovery, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia.
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2
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Shahidi M, Abazari O, Dayati P, Haghiralsadat BF, Oroojalian F, Tofighi D. Targeted delivery of 5-fluorouracil, miR-532-3p, and si-KRAS to the colorectal tumor using layer-by-layer liposomes. Front Bioeng Biotechnol 2022; 10:1013541. [PMID: 36324898 PMCID: PMC9618699 DOI: 10.3389/fbioe.2022.1013541] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 09/22/2022] [Indexed: 09/07/2024] Open
Abstract
Co-delivery of siRNA or miRNA with chemotherapeutic drugs into tumor sites is an attractive synergetic strategy for treating colorectal cancer (CRC) due to their complementary mechanisms. In the current work, a liposome nanoparticle (Huang et al., Cancer Metastasis Rev., 2018, 37, 173-187) coated by cationic chitosan (CS) using a controlled layer-by-layer (LbL) process was designed to deliver simultaneous si-KRAS, miRNA-532-3p, and 5-Fluorouracil (5-FU) into CRC cells. The LbL NPs exhibited a spherical structure with an average size of 165.9 nm and effectively protected si-KRAS and miRNA-532-3p against degradation by serum and nucleases. Interestingly, the LbL NPs were successfully entered into cells and efficiently promoted cytotoxicity and suppressed cancer cell migration and invasion. In vivo, the LbL NPs reduced tumor growth in SW480-tumor-bearing mice models. In conclusion, these results suggested that the LbL NPs co-loaded with 5-FU and miR-532-3p/si-KRAS might provide a promising potential strategy for inhibiting the malignant phenotypes of CRC cells.
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Affiliation(s)
- Maryamsadat Shahidi
- Department of Clinical Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Omid Abazari
- Department of Clinical Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Parisa Dayati
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Bibi Fatemeh Haghiralsadat
- Medical Nanotechnology and Tissue Engineering Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fatemeh Oroojalian
- Department of Advanced Technologies, School of Medicine, North Khorasan University of Medical Sciences, Bojnūrd, Iran
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Davood Tofighi
- Department of Psychology, University of New Mexico, Albuquerque, NM, United States
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3
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Li L, Wang M, Yang H, Li Y, Huang X, Guo J, Liu Z. Fisetin Inhibits Trypsin Activity and Suppresses the Growth of Colorectal Cancer in Vitro and in Vivo. Nat Prod Commun 2022. [DOI: 10.1177/1934578x221115511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Colorectal cancer (CRC) is a malignant tumor with high incidence and bad prognosis. Therapies, which are more safe and effective, are urgently needed. Trypsin is proved to be crucial to cancer proliferation and migration, therefore, it is possible to control cancers by modulating its activity. Fisetin is a flavone with trypsin inhibition properties that was screened from more than 45 compounds derived from traditional Chinese medicine (TCM). However, the effects and mechanisms of fisetin on CRC have not been well investigated. In this study, we evaluated the effects of fisetin on 2 different CRC cell lines. Fisetin remarkably inhibited CRC cell proliferation and migration, as well as induced cell apoptosis and Go/G1 phase arrest in a dose-dependent manner. Mechanistic studies revealed that these effects were mediated partially through signaling pathways involving cell cycle regulators p21, p27, cyclinD1, and NF kappa B (NF-κB) p65. Administration of fisetin also significantly suppressed the tumor growth in tumor-bearing NOD/Shi-scid-IL2R gamma (null) (NOG) mice that had been inoculated with human HCT116 cells. Fisetin at the given dosage did not induce significant acute or chronic toxicity in rats. These data provide a potential therapeutic strategy for CRC.
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Affiliation(s)
- Lin Li
- Jinan University, Guangzhou, China
| | - Min Wang
- Jinan University, Guangzhou, China
| | - Hongyan Yang
- School of Medicine, Foshan University, Foshan, China
| | | | | | - Jialiang Guo
- Jinan University, Guangzhou, China
- School of Medicine, Foshan University, Foshan, China
| | - Zheng Liu
- School of Medicine, Foshan University, Foshan, China
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4
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Cao YH, Ding J, Tang QH, Zhang J, Huang ZY, Tang XM, Liu JB, Ma YS, Fu D. Deciphering cell-cell interactions and communication in the tumor microenvironment and unraveling intratumoral genetic heterogeneity via single-cell genomic sequencing. Bioengineered 2022; 13:14974-14986. [PMID: 37105769 DOI: 10.1080/21655979.2023.2185434] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2023] Open
Abstract
A tumor's heterogeneity has important implications in terms of its clonal origin, progression, stemness, and drug resistance. Therefore, because of its significance in treatment, it is important to understand the gene expression pattern of a single cell, track gene expression or mutation in heterogeneous cells, evaluate the clonal origin of cancer cells, and determine the selective evolution of different subpopulations of cancer cells. Researchers are able to trace a cell's mutation and identify different types of tumor cells by measuring the whole transcriptome with single-cell sequencing (scRNA-seq). This technology provides a better understanding of the molecular mechanisms driving tumor growth than that offered by traditional RNA sequencing methods. In addition, it has revealed changes in the mutations and functions of somatic cells as a tumor evolves; it has also clarified immune cell infiltration and activation. Research on scRNA-seq technology has recently advanced significantly, suggesting new strategies for the treatment of cancer. In short, cancer researchers have become increasingly dependent on scRNA-seq. This paper reviews the development, detection principles, and processes of scRNA-seq technology and their application in tumor research. It also considers potential clinical applications.
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Affiliation(s)
- Ya-Hong Cao
- Department of Respiratory, Nantong Traditional Chinese Medicine Hospital, Affiliated Nantong Traditional Chinese Medicine Hospital of Nantong University, Nantong, Jiangsu, China
| | - Jie Ding
- Department of Clinical Laboratory, Jingjiang Traditional Chinese Medicine Hospital, Jingjiang, Jiangsu, China
| | - Qing-Hai Tang
- Hunan Key Laboratory for Conservation and Utilization of Biological Resources in the Nanyue Mountainous Region and College of Life Sciences and Environment, Hengyang Normal University, Hengyang, Hunan, China
| | - Jie Zhang
- Department of Immunology, School of Medicine, Nantong University, Nantong, Jiangsu, China
| | - Zhong-Yan Huang
- Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, Huangpu, China
| | - Xiao-Mei Tang
- Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, Huangpu, China
| | - Ji-Bin Liu
- Institute of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu, China
| | - Yu-Shui Ma
- Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, Xuhui, China
| | - Da Fu
- Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, Huangpu, China
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Li H, Huang B. <em>miR-19a</em> targeting <em>CLCA4</em> to regulate the proliferation, migration, and invasion of colorectal cancer cells. Eur J Histochem 2022; 66. [PMID: 35266369 PMCID: PMC8958453 DOI: 10.4081/ejh.2022.3381] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 02/19/2022] [Indexed: 12/24/2022] Open
Abstract
The role of miR-19a in colorectal cancer (CRC), a devastating disease with high mortality and morbidity, remains controversial. In the present study, we show that the level of miR-19a is significantly higher in clinical CRC tissue samples than in paracancerous tissue samples, and significantly higher in CRC cells lines HT29, SW480, and CaCO2 than in the normal human colon mucosal epithelial cell line NCM460. miR-19a mimics and inhibitors were synthesized and validated. Overexpression of miR-19a mimics significantly promoted, while miR-19a inhibitors inhibited, the proliferation, survival, migration, and invasion of SW480 and CaCO2 CRC cells. Furthermore, mRNA and protein levels of chloride channel accessory 4 (CLCA4) were lower in CRC cells and tissues. Bioinformatics and a luciferase reporter assay confirmed that CLCA4 was a miR-19a target. Further, miR-19a inhibition increased CLCA4 expression. The inhibitory effect of miR-19a on cell growth, survival, migration, and invasion was reversed by knockdown of CLCA4 expression. The data demonstrated that the miR-19a/CLCA4 axis modulates phospho-activation of the PI3K/AKT pathway in CRC cells. In conclusion, our results revealed that miR-19a overexpression decreases CLCA4 levels to promote CRC oncogenesis, suggesting that miR-19a inhibitors have potential applications for future therapeutic of CRC.
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Affiliation(s)
- Huiwen Li
- Department of Pediatrics, the First Affiliated Hospital of Jinan University, Guangzhou; Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou.
| | - Bo Huang
- Department of Gastrointestinal Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou.
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6
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Zhdanovskaya N, Firrincieli M, Lazzari S, Pace E, Scribani Rossi P, Felli MP, Talora C, Screpanti I, Palermo R. Targeting Notch to Maximize Chemotherapeutic Benefits: Rationale, Advanced Strategies, and Future Perspectives. Cancers (Basel) 2021; 13:cancers13205106. [PMID: 34680255 PMCID: PMC8533696 DOI: 10.3390/cancers13205106] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/03/2021] [Accepted: 10/06/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary The Notch signaling pathway regulates cell proliferation, apoptosis, stem cell self-renewal, and differentiation in a context-dependent fashion both during embryonic development and in adult tissue homeostasis. Consistent with its pleiotropic physiological role, unproper activation of the signaling promotes or counteracts tumor pathogenesis and therapy response in distinct tissues. In the last twenty years, a wide number of studies have highlighted the anti-cancer potential of Notch-modulating agents as single treatment and in combination with the existent therapies. However, most of these strategies have failed in the clinical exploration due to dose-limiting toxicity and low efficacy, encouraging the development of novel agents and the design of more appropriate combinations between Notch signaling inhibitors and chemotherapeutic drugs with improved safety and effectiveness for distinct types of cancer. Abstract Notch signaling guides cell fate decisions by affecting proliferation, apoptosis, stem cell self-renewal, and differentiation depending on cell and tissue context. Given its multifaceted function during tissue development, both overactivation and loss of Notch signaling have been linked to tumorigenesis in ways that are either oncogenic or oncosuppressive, but always context-dependent. Notch signaling is critical for several mechanisms of chemoresistance including cancer stem cell maintenance, epithelial-mesenchymal transition, tumor-stroma interaction, and malignant neovascularization that makes its targeting an appealing strategy against tumor growth and recurrence. During the last decades, numerous Notch-interfering agents have been developed, and the abundant preclinical evidence has been transformed in orphan drug approval for few rare diseases. However, the majority of Notch-dependent malignancies remain untargeted, even if the application of Notch inhibitors alone or in combination with common chemotherapeutic drugs is being evaluated in clinical trials. The modest clinical success of current Notch-targeting strategies is mostly due to their limited efficacy and severe on-target toxicity in Notch-controlled healthy tissues. Here, we review the available preclinical and clinical evidence on combinatorial treatment between different Notch signaling inhibitors and existent chemotherapeutic drugs, providing a comprehensive picture of molecular mechanisms explaining the potential or lacking success of these combinations.
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Affiliation(s)
- Nadezda Zhdanovskaya
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Mariarosaria Firrincieli
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Center for Life Nano Science, Istituto Italiano di Tecnologia, 00161 Rome, Italy
| | - Sara Lazzari
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Eleonora Pace
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Pietro Scribani Rossi
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Maria Pia Felli
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
| | - Claudio Talora
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Isabella Screpanti
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Correspondence: (I.S.); (R.P.)
| | - Rocco Palermo
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Center for Life Nano Science, Istituto Italiano di Tecnologia, 00161 Rome, Italy
- Correspondence: (I.S.); (R.P.)
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7
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Zhang C, Chen Y, Li F, Yang M, Meng F, Zhang Y, Chen W, Wang W. B7-H3 is spliced by SRSF3 in colorectal cancer. Cancer Immunol Immunother 2021; 70:311-321. [PMID: 32719950 PMCID: PMC10991627 DOI: 10.1007/s00262-020-02683-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 07/22/2020] [Indexed: 02/07/2023]
Abstract
B7-H3, an important co-inhibitor, is abnormally highly expressed in a variety of malignancies. The antibodies targeting B7-H3 have exhibited beneficial therapeutic effects in clinical trials. Therefore, discovery of the regulatory factors in B7-H3 expression may provide new strategies for tumor therapy. Here, we investigated the splicing factors involved in the splicing of B7-H3. By individual knockdown of the splicing factors in colorectal cancer (CRC) cells, we found that B7-H3 expression was markedly inhibited by SRSF3 and SRSF8, especially SRSF3. Then we found that both SRSF3 and B7-H3 were highly expressed in CRC tissues. Moreover, high-expression of either SRSF3 or B7-H3 was significantly correlated with poor prognosis of patients. The expression of B7-H3 mRNA and protein were evidently reduced by SRSF3 silence, but were enhanced by overexpression of SRSF3 in both HCT-116 and HCT-8 cells. The results from the RNA immunoprecipitation (RIP) assays demonstrated that SRSF3 protein directly binds to B7-H3 mRNA. In addition, we constructed a minigene recombinant plasmid for expressing B7-H3 exons 3-6. We found that SRSF3 contributed to the retention of B7-H3 exon 4. These findings demonstrate that SRSF3 involves in the splicing of B7-H3 by directly binding to its exon 4 and/or 6. It may provide novel insights into the regulatory mechanisms of B7-H3 expression and potential strategies for the treatment of CRC.
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Affiliation(s)
- Chunxia Zhang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, 215006, China
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Yinshuang Chen
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Fuchao Li
- Department of Gerontology, The Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, 210008, China
| | - Man Yang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Fanyi Meng
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Yawen Zhang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China
| | - Weichang Chen
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, 215006, China.
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Shizhi Street 188, Suzhou, 215006, China.
| | - Weipeng Wang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China.
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, 215006, China.
- Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
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8
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Pan DC, Krishnan V, Salinas AK, Kim J, Sun T, Ravid S, Peng K, Wu D, Nurunnabi M, Nelson JA, Niziolek Z, Guo J, Mitragotri S. Hyaluronic acid-doxorubicin nanoparticles for targeted treatment of colorectal cancer. Bioeng Transl Med 2021; 6:e10166. [PMID: 33532580 PMCID: PMC7823125 DOI: 10.1002/btm2.10166] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 05/04/2020] [Accepted: 05/09/2020] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer, common in both men and women, occurs when tumors form in the linings of the colon. Common treatments of colorectal cancer include surgery, chemotherapy, and radiation therapy; however, many colorectal cancer treatments often damage healthy tissues and cells, inducing severe side effects. Conventional chemotherapeutic agents such as doxorubicin (Dox) can be potentially used for the treatment of colorectal cancer; however, they suffer from limited targeting and lack of selectivity. Here, we report that doxorubicin complexed to hyaluronic acid (HA) (HA-Dox) exhibits an unusual behavior of high accumulation in the intestines for at least 24 hr when injected intravenously. Intravenous administrations of HA-Dox effectively preserved the mucosal epithelial intestinal integrity in a chemical induced colon cancer model in mice. Moreover, treatment with HA-Dox decreased the expression of intestinal apoptotic and inflammatory markers. The results suggest that HA-Dox could effectively inhibit the development of colorectal cancer in a safe manner, which potentially be used a promising therapeutic option.
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Affiliation(s)
- Daniel C. Pan
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Vinu Krishnan
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Alyssa K. Salinas
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Jayoung Kim
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Tao Sun
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Sagi Ravid
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Kevin Peng
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Debra Wu
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Md Nurunnabi
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Jeffery A. Nelson
- Faculty of Arts and Sciences, Division of SciencesHarvard UniversityCambridgeMassachusettsUSA
| | - Zachary Niziolek
- Faculty of Arts and Sciences, Division of SciencesHarvard UniversityCambridgeMassachusettsUSA
| | - Junling Guo
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
| | - Samir Mitragotri
- School of Engineering & Applied Sciences, Harvard UniversityWyss Institute of Biologically Inspired EngineeringCambridgeMassachusettsUSA
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SNORA71A Promotes Colorectal Cancer Cell Proliferation, Migration, and Invasion. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8284576. [PMID: 33083486 PMCID: PMC7559222 DOI: 10.1155/2020/8284576] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 09/01/2020] [Accepted: 09/07/2020] [Indexed: 12/24/2022]
Abstract
Small nucleolar RNAs (snoRNAs) play a crucial role during colorectal cancer (CRC) development. The study of SNORA71A is few, and its role in CRC is unknown. This study focused on screening abnormal snoRNAs in CRC and exploring the role of key snoRNA in CRC. The expression pattern of snoRNAs in 3 CRC and 3 normal colon tissues was detected via small RNA sequencing. The six candidate snoRNAs were identified by quantitative PCR (qPCR). Subsequently, the expression level of SNORA71A was further verified through the Cancer Genome Atlas (TCGA) data analysis and qPCR. The CCK8 and transwell assays were used to detect the functional role of SNORA71A in CRC cells. The integrated analysis of snoRNA expression profile indicated that a total 107 snoRNAs were significantly differentially expressed (DE) in CRC tissues compared with normal tissues, including 45 upregulated and 62 downregulated snoRNAs. Bioinformatics analysis revealed that the DE snoRNAs were mainly implicated in "detection of chemical stimulus involved in sensory perception of smell" and "sensory perception of smell" in the biological process. The DE snoRNAs were preferentially enriched in "olfactory transduction" and "glycosphingolipid biosynthesis-ganglio series pathway." The expression of SNORA71A was upregulated in CRC tissues and cells. SNORA71A expression showed statistically significant correlations with TNM stage (P = 0.0196) and lymph node metastasis (P = 0.0189) and can serve as biomarkers for CRC. Importantly, SNORA71A significantly facilitated the CRC cell proliferation, migration, and invasion. Our findings indicate that SNORA71A screened by sequencing acted as an oncogene and promoted proliferation, migration, and invasion ability of CRC cells.
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10
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Gonulcu SC, Unal B, Bassorgun IC, Ozcan M, Coskun HS, Elpek GO. Expression of Notch pathway components (Numb, Itch, and Siah-1) in colorectal tumors: A clinicopathological study. World J Gastroenterol 2020; 26:3814-3833. [PMID: 32774060 PMCID: PMC7383841 DOI: 10.3748/wjg.v26.i26.3814] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/18/2020] [Accepted: 06/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The role of the Notch pathway in carcinogenesis and tumor progression has been demonstrated in many organs, including the colon. Accordingly, studies aimed at developing therapies targeting this pathway in various cancers require the identification of several factors that may play a role in regulating Notch-1 expression. Although Numb, Itch, and seven in absentia homolog-1 (Siah-1) have been shown to contribute to the regulation of Notch signaling, their role in colorectal carcinogenesis and tumor progression has not been fully elucidated to date.
AIM To evaluate Numb, Itch, and Siah-1 expression in colorectal tumors to clarify their relationship with Notch-1 expression and their role in carcinogenesis and tumor behavior.
METHODS Expression of Notch-1, Numb, Itch, and Siah-1 was investigated in 50 colorectal carcinomas, 30 adenomas, and 20 healthy colonic tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (PCR) analyses.
RESULTS In contrast to Notch-1, which is expressed at higher levels in tumor tissues and adenomas, expression of Numb, Itch, and Siah-1 was stronger and more frequent in normal mucosa (P < 0.01). There was a positive correlation between Notch-1 expression and high histological grade, the presence of lymph node metastasis, and advanced-stage tumors, whereas expression of Numb, Itch, and Siah-1 was absent or reduced in tumors with these clinicopathological parameters (P < 0.05). In survival analysis, expression of Notch was related to poor prognosis but that of Numb, Itch, and Siah-1 correlated with improved survival (P < 0.05). Multivariate analysis revealed Notch-1 expression and loss of Numb expression to be independent prognostic parameters together with lymph node metastasis (P < 0.05).
CONCLUSION Our findings support the role of Notch-1 in colorectal carcinoma and indicate that loss of Numb, Itch, and Siah-1 expression is associated with carcinogenesis. Our data also suggest that these three proteins might be involved in the Notch-1 pathway during colorectal carcinoma (CRC) progression and might play an essential role in approaches targeting Notch as novel molecular therapies for CRC.
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Affiliation(s)
- Sinem Cil Gonulcu
- Department of Pathology, Akdeniz University, School of Medicine, Antalya 07070, Turkey
| | - Betul Unal
- Department of Pathology, Akdeniz University, School of Medicine, Antalya 07070, Turkey
| | | | - Mualla Ozcan
- Department of Pathology, Akdeniz University, School of Medicine, Antalya 07070, Turkey
| | - Hasan Senol Coskun
- Department of Oncology, Akdeniz University, School of Medicine, Antalya 07070, Turkey
| | - Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University, School of Medicine, Antalya 07070, Turkey
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Jiao Q, Ren Y, Ariston Gabrie AN, Wang Q, Wang Y, Du L, Liu X, Wang C, Wang YS. Advances of immune checkpoints in colorectal cancer treatment. Biomed Pharmacother 2020; 123:109745. [DOI: 10.1016/j.biopha.2019.109745] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 12/04/2019] [Accepted: 12/05/2019] [Indexed: 12/30/2022] Open
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12
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Spartalis C, Schmidt EM, Elmasry M, Schulz GB, Kirchner T, Horst D. In vivo effects of chemotherapy on oncogenic pathways in colorectal cancer. Cancer Sci 2019; 110:2529-2539. [PMID: 31119819 PMCID: PMC6676136 DOI: 10.1111/cas.14077] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 05/06/2019] [Accepted: 05/20/2019] [Indexed: 12/22/2022] Open
Abstract
Patients with advanced colorectal cancer often are treated with systemic cytotoxic therapy using fluorouracil (5‐FU), oxaliplatin, irinotecan, and FOLFOX or FOLFIRI combination protocols. Additionally, signaling pathways that are active in colorectal cancer can be therapeutically targeted. Herein, we examined whether chemotherapy impacts on WNT, MAPK and NOTCH signaling pathways in xenograft models of colon cancer. Furthermore, we tested whether combining chemotherapy with MAPK and NOTCH inhibition has superior therapeutic effects. We show that colon cancer cells with high WNT, MAPK and NOTCH activity are variably affected but generally persist in xenograft tumors under different chemotherapeutic regimens, indicating limited effects of cytotoxic therapy on oncogenic signaling pathways. Although these results provided a rationale to additionally target pathway activity, we found no significant increase in therapy response when combining MAPK and NOTCH inhibition with fluorouracil chemotherapy. We attribute this finding to a decrease in tumor cell proliferation upon MAPK and NOTCH inhibition, resulting in reduced effectiveness of cytotoxic treatment. Therapeutic benefits of combining chemotherapy with targeting of oncogenic signaling pathways must therefore be critically evaluated for patients with colorectal cancer.
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Affiliation(s)
- Christoph Spartalis
- Institute of Pathology, Ludwig-Maximilians-Universität Munich, Munich, Germany
| | - Eva Marina Schmidt
- Institute of Pathology, Ludwig-Maximilians-Universität Munich, Munich, Germany
| | - Manal Elmasry
- Institute of Pathology, Ludwig-Maximilians-Universität Munich, Munich, Germany
| | | | - Thomas Kirchner
- Institute of Pathology, Ludwig-Maximilians-Universität Munich, Munich, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - David Horst
- Institute of Pathology, Ludwig-Maximilians-Universität Munich, Munich, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
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