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Yang Y, Zhang C, Li H, He Q, Xie J, Liu H, Cui F, Lei Z, Qin X, Liu Y, Xu M, Huang S, Zhang X. A review of molecular interplay between inflammation and cancer: The role of lncRNAs in pathogenesis and therapeutic potential. Int J Biol Macromol 2025; 309:142824. [PMID: 40187457 DOI: 10.1016/j.ijbiomac.2025.142824] [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: 01/17/2025] [Revised: 03/31/2025] [Accepted: 04/02/2025] [Indexed: 04/07/2025]
Abstract
The inflammatory microenvironment (IME) has been demonstrated to facilitate the initiation and progression of tumors throughout the inflammatory process. Simultaneously, cancer can initiate or intensify the inflammatory response, thereby promoting tumor progression. This review examines the dual role of long non-coding RNAs (lncRNAs) in the interplay between inflammation and cancer. LncRNA modulate inflammation-induced cancer by influencing the activation of signaling pathways (NF-κB, Wnt/β-catenin, mTOR, etc), microRNA (miRNA) sponging, protein interactions, interactions with immune cells, and encoding short peptides. In contrast, lncRNAs also impact cancer-induced inflammatory processes by regulating cytokine expression, mediating tumor-derived extracellular vesicles (EVs), modulating intracellular reactive oxygen species (ROS) levels, and facilitating metabolic reprogramming. Furthermore, the therapeutic potential of lncRNA and the challenges of clinical translation were explicitly discussed as well. Overall, this review aims to provide a comprehensive and systematic resource for future researchers investigating the impact of lncRNAs on inflammation and cancer.
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Affiliation(s)
- Yan Yang
- Department of Pharmacy, The Third People's Hospital of Chengdu, Chengdu, China; School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China
| | - Chuxi Zhang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China
| | - Huacui Li
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China; Tangshan Institute of Southwest Jiaotong University, Tangshan, China
| | - Qin He
- Department of Pharmacy, The Third People's Hospital of Chengdu, Chengdu, China
| | - Jiang Xie
- Department of Pediatrics, The Third People's Hospital of Chengdu, Chengdu, China
| | - Hongmei Liu
- Department of Pharmacy, The Third People's Hospital of Chengdu, Chengdu, China
| | - Fenfang Cui
- Department of Pharmacy, The Third People's Hospital of Chengdu, Chengdu, China
| | - Ziqin Lei
- Department of Pharmacy, The Third People's Hospital of Chengdu, Chengdu, China
| | - Xiaoyan Qin
- Department of Pharmacy, The Third People's Hospital of Chengdu, Chengdu, China
| | - Ying Liu
- Department of Pharmacy, The Third People's Hospital of Chengdu, Chengdu, China
| | - Min Xu
- Department of Pharmacy, The Third People's Hospital of Chengdu, Chengdu, China.
| | - Shuai Huang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China.
| | - Xu Zhang
- Department of Pharmacy, Chengdu Integrated TCM & Western Medicine Hospital, Chengdu University of TCM, Chengdu, China.
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Huang D, Lin D, Liang S, Lin J. Expression of CXCR4 in the Primary Lesion of Recurrent Metastatic Breast Cancer and Its Association With Prognosis. Int J Gen Med 2025; 18:1543-1553. [PMID: 40123816 PMCID: PMC11929416 DOI: 10.2147/ijgm.s511426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 02/12/2025] [Indexed: 03/25/2025] Open
Abstract
Objective This study examined CXCR4 expression in primary lesions of recurrent metastatic breast cancer patients, analyzing its association with clinicopathological features, chemotherapy efficacy, and prognosis. Methods Eighty-five early surgical specimens of advanced BCa were examined for CXCR4 expression using immunohistochemical staining. The relationships between CXCR4 expression and clinical pathological factors, such as tumor size, lymph node metastasis, tumor stage, and metastatic site, were statistically analyzed, along with their effect on the efficacy of platinum-based chemotherapy and prognosis in patients with advanced BCa. Results Significant associations were found between high CXCR4 levels in primary lesions of recurrent metastatic BCa and more frequent visceral metastases (p = 0.010), along with a higher rate of lymph node metastases (p = 0.022). Patients with advanced BCa showing high CXCR4 expression had lower efficacy with platinum-based chemotherapy (p = 0.002). Patients with high CXCR4 expression exhibited shorter disease-free survival (DFS) and overall survival (OS) compared to those with low expression, though the differences lacked statistical significance. Conclusion Patients with recurrent metastatic BCa with high expression of CXCR4 in primary lesions have poor efficacy with platinum-based chemotherapy, shorter DFS and OS, and poor prognosis. CXCR4 may be an important biomarker in metastatic BCa. It can be used not only as a predictor of metastasis and prognosis, but also as a therapeutic target and a tool to monitor treatment efficacy.
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Affiliation(s)
- DanChan Huang
- Department of Oncology, The First Affiliated Hospital of Shantou University Medical College, Shantou City, Guangdong Province, 515000, People’s Republic of China
| | - DanXia Lin
- Department of Breast Oncology, Cancer Hospital of Shantou University Medical College, Shantou City, Guangdong Province, 515000, People’s Republic of China
| | - SiXian Liang
- Department of Breast Oncology, Cancer Hospital of Shantou University Medical College, Shantou City, Guangdong Province, 515000, People’s Republic of China
| | - Jing Lin
- Department of Oncology, The First Affiliated Hospital of Shantou University Medical College, Shantou City, Guangdong Province, 515000, People’s Republic of China
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3
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Qin Y, Miyake T, Muramoto K, Maekawa T, Nishina Y, Wang Y, Shimizu T, Tani M. Fibroblast Activation Protein-α Expression in Cancer-Associated Fibroblasts Shows the Poor Survival of Colorectal Cancer via Immune-Mediated Pathways : Implications of FAP in Cancer-Associated Fibroblasts Link Immune Dysregulation to Adverse Survival in Colorectal Cancer. Ann Surg Oncol 2025; 32:1941-1952. [PMID: 39623187 DOI: 10.1245/s10434-024-16593-y] [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: 08/21/2024] [Accepted: 11/12/2024] [Indexed: 02/12/2025]
Abstract
BACKGROUND Cancer-associated fibroblasts (CAFs) and immune cells, the key components of the tumor microenvironment (TME), play critical roles in oncogenesis. Despite the recognized function of fibroblast activation protein-α (FAP), a specific biomarker of CAFs in cancer progression, its role in the survival of patients with colorectal cancer (CRC) and tumor immune microenvironment (TIME) remains unclear. METHODS We investigated 180 pathological sections obtained from 178 consecutive patients with CRC who underwent surgical resection at Shiga University of Medical Science Hospital between January 2013 and December 2015. FAP expression levels and CD3 and CD8 densities at the invasive margin and center of tumor were assessed using immunohistochemical (IHC) staining. Furthermore, we used single-cell RNA sequencing (scRNA-seq) of CAFs in a separate cohort of 10 untreated patients with CRC derived from the Gene Expression Omnibus database. RESULTS According to IHC evaluation, high FAP expression in patients with CRC showed a correlation with reduced tumor-infiltrating lymphocyte (TIL) distribution and poor survival. Based on the FAP transcription levels obtained through scRNA-seq analysis, CAFs were grouped into high and low FAP expression groups. Elevated FAP expression was correlated with decreased expression of T- and B-cell biomarkers, suggesting an association with an immunosuppressive TME promotion. Several genes associated with cancer-related immune-mediated pathways (CXCL12, COL11A1, CCL11, and COL10A1) were significantly upregulated in FAP-positive CAFs. CONCLUSIONS This study highlights the effects of FAP expression on survival of patients with CRC, its interaction with TILs, and relevant signaling pathways, and underscores potential immunotherapeutic targets for future investigation.
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Affiliation(s)
- Yubo Qin
- Department of Surgery, Shiga University of Medical Science, Shiga, Japan
- Department of Emergency Center, Inner Mongolia Autonomous Region People's Hospital, Hohhot, China
| | - Toru Miyake
- Department of Surgery, Shiga University of Medical Science, Shiga, Japan.
| | - Keiji Muramoto
- Department of Surgery, Shiga University of Medical Science, Shiga, Japan
| | - Takeru Maekawa
- Department of Surgery, Shiga University of Medical Science, Shiga, Japan
| | - Yusuke Nishina
- Department of Surgery, Shiga University of Medical Science, Shiga, Japan
| | - Ying Wang
- Department of Surgery, Shiga University of Medical Science, Shiga, Japan
| | - Tomoharu Shimizu
- Department of Surgery, Shiga University of Medical Science, Shiga, Japan
| | - Masaji Tani
- Department of Surgery, Shiga University of Medical Science, Shiga, Japan
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Ayeldeen G, Badr BM, Shaker OG, Diab K, Ahmed TI, Hassan EA, Nagaty RA, Galal S, Hasona NA. Integrated analysis of non‑coding RNAs (HOTAIR and miR‑130a) and their cross‑talk with TGF‑β1, SIRT1 and E‑cadherin as potential biomarkers in colorectal cancer. Oncol Lett 2025; 29:116. [PMID: 39807105 PMCID: PMC11726295 DOI: 10.3892/ol.2025.14863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 11/15/2024] [Indexed: 01/16/2025] Open
Abstract
Molecular changes have a substantial impact on the onset of colorectal cancer (CRC). Complexes of HOTAIR and miRNAs disrupt several cellular functions during carcinogenesis, primarily by disrupting several carcinogenic signaling pathways. In the present study, the relationships between the serum levels of transforming growth factor-β1 (TGF-β1), sirtuin-1 (SIRT1) and E-cadherin and those of HOX transcript antisense intergenic RNA (HOTAIR) and microRNA-130a (miR-130a) in individuals with CRC were analyzed, including their correlations and diagnostic potential. Patients with colon cancer and healthy volunteers were enrolled in the study. Blood samples were collected from 70 patients with CRC and 30 age-matched healthy control volunteers and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to determine the serum levels of HOTAIR and miR-130a. In addition, the levels of TGF-β1, SIRT1 and E-cadherin were determined utilizing enzyme-linked immunosorbent assays. Patients with CRC were found to have significantly higher TGF-β1, SIRT1, HOTAIR and miR-130a serum levels than those of healthy participants. In addition, patients with high-grade CRC had significantly higher levels of TGF-β1, SIRT1, HOTAIR and miR-130a compared with those of patients with low-grade CRC. A significant reduction in the serum levels of E-cadherin was observed in participants with CRC compared with healthy participants, but no significant difference was detected according to the grade of CRC. Positive correlations were found between HOTAIR and miR-130a, as well as TGF-β1 and SIRT1. By contrast, negative correlations were noted between E-cadherin and HOTAIR, miR-130a, TGF-β1 and SIRT1. Therefore, it may be concluded that the miR-130a/HOTAIR and TGF-β1/SIRT1/E-cadherin axes may serve as novel biomarkers for the early diagnosis of CRC.
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Affiliation(s)
- Ghada Ayeldeen
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza 12613, Egypt
| | - Bahaa Mohammed Badr
- Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Al-Azhar University (Assiut branch), Assiut 71524, Egypt
| | - Olfat G. Shaker
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza 12613, Egypt
| | - Khaled Diab
- Department of General Surgery, Faculty of Medicine, Fayoum University, Fayoum 63514, Egypt
| | - Tarek I. Ahmed
- Department of Internal Medicine, Faculty of Medicine, Fayoum University, Fayoum 63514, Egypt
| | - Essam A. Hassan
- Department of Tropical Medicine, Faculty of Medicine, Fayoum University, Fayoum 63514, Egypt
| | - Raghda A. Nagaty
- Clinical and Chemical Pathology Research Institute of Ophthalmology, Ministry of Higher Education and Scientific Research, Cairo 11694, Egypt
| | - Shaymaa Galal
- Department of Biochemistry, Modern University for Technology and Information, Cairo 11792, Egypt
| | - Nabil A. Hasona
- Department of Biochemistry, Faculty of Science, Beni-Suef University, Beni-Suef 62511, Egypt
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Tetrick MG, Emon MAB, Doha U, Marcellus M, Symanski J, Ramanathan V, Saif MTA, Murphy CJ. Decoupling chemical and mechanical signaling in colorectal cancer cell migration. Sci Rep 2025; 15:4952. [PMID: 39929899 PMCID: PMC11811049 DOI: 10.1038/s41598-025-89152-4] [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: 10/13/2024] [Accepted: 02/03/2025] [Indexed: 02/13/2025] Open
Abstract
Colorectal cancer metastasis is governed by a variety of chemical and mechanical signaling that are largely influenced by cancer-associated fibroblasts (CAFs) in the tumor microenvironment. Here, we deconvolute the chemical from mechanical signaling in the case of the colon cancer cell line HCT-116 and CAFs. We examined three chemoattractants (CXCL12, TGF-β, and activin A) which allegedly are secreted by CAFs and induce HCT-116 cell migration. None of the chemoattractants tested resulted in enhanced migration of HCT-116 in a 2D transwell assay, at low cell density. Similarly, CAF-conditioned media also did not lead to enhanced HCT-116 migration, while CAFs co-cultured in the transwell assay did lead to increased HCT-116 migration. This result suggests that either high cell densities are required for chemotaxis, and/or a reciprocal two-way signaling network between CAFs and HCT-116 is necessary to induce chemotaxis. Surprisingly, we find that HCT-116 cells exhibit enhanced migration along the axis of mechanical stress in a 3D collagen matrix, at very high cell densities. This migration is independent of whether the strain is induced mechanically or by CAFs. By comparing purely mechanical and purely chemical migration to a 3D co-culture of CAFs and HCT-116 containing both chemical and mechanical cues, it is concluded that HCT-116 migration is dominated by mechanical signaling, while chemical cues are less influential.
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Affiliation(s)
- Maxwell G Tetrick
- Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Md Abul Bashar Emon
- Department of Mechanical Science and Engineering, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Umnia Doha
- Department of Mechanical Science and Engineering, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Marsophia Marcellus
- Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Joseph Symanski
- Department of Mechanical Science and Engineering, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Valli Ramanathan
- Department of Chemical and Biomolecular Engineering, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - M Taher A Saif
- Department of Mechanical Science and Engineering, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA
| | - Catherine J Murphy
- Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA.
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Sun Y, Kong D, Zhang Q, Xiang R, Lu S, Feng L, Zhang H. DNA methylation biomarkers for predicting lymph node metastasis in colorectal cancer. Clin Transl Oncol 2025; 27:439-448. [PMID: 39026026 DOI: 10.1007/s12094-024-03601-6] [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: 05/05/2024] [Accepted: 07/06/2024] [Indexed: 07/20/2024]
Abstract
Colorectal cancer is one of the most common cancers worldwide. Lymph node metastasis is an important marker of colorectal cancer progression and plays a key role in the evaluation of patient prognosis. Accurate preoperative assessment of lymph node metastasis is crucial for devising appropriate treatment plans. However, current clinical imaging methods have limitations in many aspects. Therefore, the discovery of a method for accurately predicting lymph node metastasis is crucial clinical decision-making. DNA methylation is a common epigenetic modification that can regulate gene expression, which also has an important impact on the development of colorectal cancer. It is considered to be a promising biomarker with good specificity and stability and has promising application in predicting lymph node metastasis in patients with colorectal cancer. This article reviews the characteristics and limitations of currently available methods for predicting lymph node metastasis in patients with colorectal cancer and discusses the role of DNA methylation as a biomarker.
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Affiliation(s)
- Yu Sun
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Deyang Kong
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Qi Zhang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Renshen Xiang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Shuaibing Lu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lin Feng
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Haizeng Zhang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Vanhie JJ, Orloff LE, Tate A, Goode C, Collao N, Pisanko A, Power KA, DE Lisio M. Obesity Promotes Marrow-Derived Myeloid Cell Accumulation While Exercise Reduces Proliferative Signaling in Colon Cancer. Med Sci Sports Exerc 2025; 57:317-326. [PMID: 39350427 DOI: 10.1249/mss.0000000000003572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2025]
Abstract
PURPOSE Obesity increases colon cancer risk that has been previously linked to marrow-derived myeloid cells. We previously demonstrated that exercise training (EX) prevents colon cancer initiation, potentially through reduced myelopoiesis. However, it remains unknown whether early myeloid cell accumulation and inflammation in the colon precedes carcinogenesis with high-fat diet (HFD)-induced obesity, and if EX can attenuate these effects. We hypothesized that obesity would promote colon carcinogenesis that was preceded by myeloid cell accumulation and inflammation that would be attenuated by EX. METHODS C57BL/6 mice were randomized to a HFD or control (CON) diet for 8 weeks. The HFD mice switched to CON diet and all mice were given intraperitoneal injections of azoxymethane (AOM) to induce colon cancer and randomized into EX or sedentary (SED) conditions. RESULTS HFD mice developed more aberrant crypt foci (ACF), a marker for early carcinogenesis, compared with CON ( P < 0.01), and EX developed fewer ACF compared with SED ( P < 0.0001). Marrow-derived ( P < 0.001) CD206 + macrophages were elevated in HFD compared with CON at study week 16 ( P < 0.01). Marrow-derived CD206 - macrophages ( P < 0.05) and marrow-derived ( P < 0.05) CD206 + macrophages were more abundant in HFD compared with CON at study week 42. EX did not alter colon immune cell populations. β-catenin protein was higher in HFD compared with CON at study week 42 ( P < 0.05), and STAT3 protein content was lower at study week 28 with EX compared with SED ( P < 0.05). CONCLUSIONS The results suggest that obesity promotes colon ACF formation, potentially through early inflammatory myeloid cell accumulation. Despite attenuating ACF, EX did not alter myeloid cell accumulation in the colon, suggesting that EX inhibits ACF formation through alternative mechanisms which may include reduced β-catenin and STAT3 signaling.
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Affiliation(s)
- James J Vanhie
- School of Human Kinetics, University of Ottawa, Ottawa, ON, CANADA
| | - Lisa Ek Orloff
- School of Human Kinetics, University of Ottawa, Ottawa, ON, CANADA
| | - Alice Tate
- School of Human Kinetics, University of Ottawa, Ottawa, ON, CANADA
| | - Cole Goode
- School of Human Kinetics, University of Ottawa, Ottawa, ON, CANADA
| | | | - Anastasia Pisanko
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, CANADA
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Khorramdelazad H, Bagherzadeh K, Rahimi A, Darehkordi A, Najafi A, Karimi M, Khoshmirsafa M, Hassanshahi G, Safari E, Falak R. A1, an innovative fluorinated CXCR4 inhibitor, redefines the therapeutic landscape in colorectal cancer. Cancer Cell Int 2025; 25:5. [PMID: 39757159 DOI: 10.1186/s12935-024-03584-y] [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: 07/08/2024] [Accepted: 11/22/2024] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a globally prevalent malignancy, primarily affecting the colon and rectum, characterized by uncontrolled cellular changes in the intestinal wall lining. Recent evidence underlines the significant role of the CXCL12/CXCR4 axis in the development of CRC, suggesting that inhibiting this pathway could be a promising therapeutic approach. This study focuses on investigating the potential of N, N''-thiocarbonylbis (N'-(3,4-dimethyl phenyl)-2,2,2-trifluoroacetimidamide) (A1), a novel fluorinated CXCR4 inhibitor, through a comprehensive analysis encompassing in silico, in vitro, and in vivo studies. METHODS The molecular dynamic simulation method was employed to compute A1 binding affinity and energy for the CXCR4 receptor compared to AMD3100. In vitro experiments utilized the CT-26 mouse CRC cell line to compare the inhibitory effects of A1 and AMD3100 on tumor cell proliferation and migration. Following the development of the CRC animal model in BALB/c mice, immune system responses within the tumor microenvironment (TME) were evaluated. Flow cytometry and real-time PCR (RT-PCR) were used to measure the effects of AMD3100 and A1 on regulatory T-cell (Treg) infiltration and the expression of CXCR4, vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF), interleukin-10 (IL-10), and tumor growth factor-beta (TGF-β) genes in tumor tissue. Additionally, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) techniques were employed to assess VEGF, IL-10, and TGF-β tissue levels at the protein level. RESULTS Molecular dynamic simulation studies with molecular mechanics Poisson-Boltsman surface area (MM-PBSA) analysis revealed that A1 exhibits significantly lower binding energy for the CXCR4 receptor than AMD3100. A1 effectively inhibited the proliferation of CT-26 cells, significantly reduced tumor cell migration, attenuated Treg infiltration, and suppressed IL-10 and TGF-β expression at both mRNA and protein levels in vivo. Notably, A1 outperformed AMD3100 in reducing tumor size and increasing survival rate in treated animals, with minimal side effects. CONCLUSION These findings emphasize the potential of A1 as a favorable anti-tumor small molecule in CRC. Further validation through rigorous preclinical and clinical studies may position A1 as a promising alternative to AMD3100 in human cancers.
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Affiliation(s)
- Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Hemmat Ave, Tehran, Iran
| | - Kowsar Bagherzadeh
- Eye Research Center, the Five Senses Health Institute, Rassoul Akram Hospital, University of Medical Sciences, Tehran, Iran
| | - Ali Rahimi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Hemmat Ave, Tehran, Iran
- Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Darehkordi
- Department of Chemistry, Faculty of Science, Vali-E-Asr University of Rafsanjan, Rafsanjan, Iran
| | - Alireza Najafi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Hemmat Ave, Tehran, Iran
- Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Milad Karimi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Hemmat Ave, Tehran, Iran
- Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Majid Khoshmirsafa
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Hemmat Ave, Tehran, Iran
- Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Gholamhossein Hassanshahi
- Molecular Medicine Research Centre, Institute of Basics Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Elaheh Safari
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Hemmat Ave, Tehran, Iran.
- Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Reza Falak
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Hemmat Ave, Tehran, Iran.
- Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran.
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9
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Bahrami A, Khalaji A, Bahri Najafi M, Sadati S, Raisi A, Abolhassani A, Eshraghi R, Khaksary Mahabady M, Rahimian N, Mirzaei H. NF-κB pathway and angiogenesis: insights into colorectal cancer development and therapeutic targets. Eur J Med Res 2024; 29:610. [PMID: 39702532 DOI: 10.1186/s40001-024-02168-w] [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: 06/11/2024] [Accepted: 11/21/2024] [Indexed: 12/21/2024] Open
Abstract
Colorectal cancer (CRC) is currently ranked as the third most common type of cancer, contributing significantly to mortality and morbidity worldwide. Epigenetic and genetic changes occurred during CRC progression resulted in the cell proliferation, cancer progression, angiogenesis, and invasion. Angiogenesis is one of the crucial steps during cancer progression required for the delivery of essential nutrients to cancer cells and removes metabolic waste. During angiogenesis, different molecules are secreted from tumoral cells to trigger vascular formation including epidermal growth factor and the vascular endothelial growth factor (VEGF). The production and regulation of the secretion of these molecules are modulated by different subcellular pathways such as NF-κB. NF-κB is involved in regulation of different homeostatic pathways including apoptosis, cell proliferation, inflammation, differentiation, tumor migration, and angiogenesis. Investigation of different aspects of this pathway and its role in angiogenesis could provide a comprehensive overview about the underlying mechanisms and could be used for development of further therapeutic targets. In this review of literature, we comprehensively reviewed the current understanding and potential of NF-κB-related angiogenesis in CRC. Moreover, we explored the treatments that are based on the NF-κB pathway.
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Affiliation(s)
- Ashkan Bahrami
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Amirreza Khalaji
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majed Bahri Najafi
- Applied Physiology Research Center, Cardiovascular Research Institute, Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sina Sadati
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Arash Raisi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Reza Eshraghi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran.
| | - Mahmood Khaksary Mahabady
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Neda Rahimian
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran.
- Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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10
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Abdul-Huseen SD, Alabassi HM. Estimate the relationship between CXCR4-SDF-1 axis and inhibitory molecules (CTLA4 and PD-1) in patients with colon cancer. NARRA J 2024; 4:e992. [PMID: 39816054 PMCID: PMC11731802 DOI: 10.52225/narra.v4i3.992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 10/21/2024] [Indexed: 01/18/2025]
Abstract
Colon neoplasia is one of the major malignancies in industrialized countries due to their Western-style food habits. It accounts for more than 50% of the population developing adenomatous polyps by the age of 70 years, but 10% of cancers in developed countries. The aim of this study was to evaluate the pathological role of the C-X-C chemokine receptor type 4/stromal-derived factor 1 axis (CXCR4-SDF-1 axis), and the inhibitory molecules PD-1 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) in postoperative colon cancer patients undergoing treatment with chemotherapy (oxaliplatin and capecitabine) and estimate the correlation between these studied factors to deeply understand the basic mechanisms and potential diagnostic or therapeutic effects. The study involved 90 patients, including 50 colon cancer patients (male and female, aged 35-65) diagnosed by oncologists at Al-Ramadi Hospital, Ramadi, Iraq. All patients underwent surgical resection and received four cycles of chemotherapy with oxaliplatin (85 mg every 21 days) and capecitabine (6 grams daily for 21 days). Additionally, 40 age- and sex-matched individuals served as the control group. For each participant, CXCR4 and SDF-1 levels were measured using ELISA and the gene expression of CTLA-4 and PD-1 were measured using RT-PCR. The colon cancer patient group showed significantly lower levels of CXCR4 and SDF-1 compared to control groups (0.163±0.012 vs 0.376±0.025 pg/mL and 0.376±0.025 vs 0.699±0.110 pg/mL, respectively, both had p=0.001). Moreover, the colon cancer patient group had significantly lower expression of PD-1 and CTLA4 compared to control group (0.102±0.029-fold vs 1.199±0.391-fold, p=0.02; and 0.302±0.140-fold vs 1.441±0.334-fold, p=0.008, respectively). In conclusion, the results suggest that CXCR4 and SDF-1 appear promising as diagnostic markers for distinguishing colon cancer patients from healthy conditions.
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Affiliation(s)
- Suhad D Abdul-Huseen
- Department of Biology, College of Education for Pure Science Ibn Al-Haitham, University of Baghdad, Baghdad, Iraq
| | - Hazima M Alabassi
- Department of Biology, College of Education for Pure Science Ibn Al-Haitham, University of Baghdad, Baghdad, Iraq
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11
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Ashouri K, Wong A, Mittal P, Torres-Gonzalez L, Lo JH, Soni S, Algaze S, Khoukaz T, Zhang W, Yang Y, Millstein J, Lenz HJ, Battaglin F. Exploring Predictive and Prognostic Biomarkers in Colorectal Cancer: A Comprehensive Review. Cancers (Basel) 2024; 16:2796. [PMID: 39199569 PMCID: PMC11353018 DOI: 10.3390/cancers16162796] [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: 06/28/2024] [Revised: 08/04/2024] [Accepted: 08/07/2024] [Indexed: 09/01/2024] Open
Abstract
Colorectal cancer (CRC) remains the second leading cause of cancer-related mortality worldwide. While immune checkpoint inhibitors have significantly improved patient outcomes, their effectiveness is mostly limited to tumors with microsatellite instability (MSI-H/dMMR) or an increased tumor mutational burden, which comprise 10% of cases. Advancing personalized medicine in CRC hinges on identifying predictive biomarkers to guide treatment decisions. This comprehensive review examines established tissue markers such as KRAS and HER2, highlighting their roles in resistance to anti-EGFR agents and discussing advances in targeted therapies for these markers. Additionally, this review summarizes encouraging data on promising therapeutic targets and highlights the clinical utility of liquid biopsies. By synthesizing current evidence and identifying knowledge gaps, this review provides clinicians and researchers with a contemporary understanding of the biomarker landscape in CRC. Finally, the review examines future directions and challenges in translating promising biomarkers into clinical practice, with the goal of enhancing personalized medicine approaches for colorectal cancer patients.
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Affiliation(s)
- Karam Ashouri
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Alexandra Wong
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Pooja Mittal
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Lesly Torres-Gonzalez
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Jae Ho Lo
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Shivani Soni
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Sandra Algaze
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Taline Khoukaz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Yan Yang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Joshua Millstein
- Department of Population and Public Health Sciences, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
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12
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Khetan R, Eldi P, Lokman NA, Ricciardelli C, Oehler MK, Blencowe A, Garg S, Pillman K, Albrecht H. Unveiling G-protein coupled receptors as potential targets for ovarian cancer nanomedicines: from RNA sequencing data analysis to in vitro validation. J Ovarian Res 2024; 17:156. [PMID: 39068454 PMCID: PMC11282829 DOI: 10.1186/s13048-024-01479-0] [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: 05/22/2024] [Accepted: 07/16/2024] [Indexed: 07/30/2024] Open
Abstract
Genetic heterogeneity in ovarian cancer indicates the need for personalised treatment approaches. Currently, very few G-protein coupled receptors (GPCRs) have been investigated for active targeting with nanomedicines such as antibody-conjugated drugs and drug-loaded nanoparticles, highlighting a neglected potential to develop personalised treatment. To address the genetic heterogeneity of ovarian cancer, a future personalised approach could include the identification of unique GPCRs expressed in cancer biopsies, matched with personalised GPCR-targeted nanomedicines, for the delivery of lethal drugs to tumour tissue before, during and after surgery. Here we report on the systematic analysis of public ribonucleic acid-sequencing (RNA-seq) gene expression data, which led to prioritisation of 13 GPCRs as candidates with frequent overexpression in ovarian cancer tissues. Subsequently, primary ovarian cancer cells derived from ascites and ovarian cancer cell lines were used to confirm frequent gene expression for the selected GPCRs. However, the expression levels showed high variability within our selection of samples, therefore, supporting and emphasising the need for the future development of case-to-case personalised targeting approaches.
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Affiliation(s)
- Riya Khetan
- Centre of Pharmaceutical Innovation, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia
| | - Preethi Eldi
- UniSA Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia
| | - Noor A Lokman
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, South Australia, 5000, Australia
| | - Carmela Ricciardelli
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, South Australia, 5000, Australia
| | - Martin K Oehler
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, South Australia, 5000, Australia
- Department of Gynaecological Oncology, Royal Adelaide Hospital, Adelaide, South Australia, 5000, Australia
| | - Anton Blencowe
- Applied Chemistry and Translational Biomaterials Group, Centre of Pharmaceutical Innovation, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia
| | - Sanjay Garg
- Centre of Pharmaceutical Innovation, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia
| | - Katherine Pillman
- Centre for Cancer Biology, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
| | - Hugo Albrecht
- Centre of Pharmaceutical Innovation, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
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13
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Zhang LL, Du MY, Du X, Duan J, Yao DM, Jing J, Feng C, Song L. Correlation analysis of human papillomavirus E6/E7 mRNA detection with diagnosis, prognosis and recurrence risk in patients with cervical epithelioma. World J Clin Cases 2024; 12:4146-4153. [PMID: 39015927 PMCID: PMC11235549 DOI: 10.12998/wjcc.v12.i20.4146] [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: 04/08/2024] [Revised: 05/13/2024] [Accepted: 05/20/2024] [Indexed: 06/30/2024] Open
Abstract
BACKGROUND Cervical intraepithelial neoplasia (CIN) is an important precursor of cervical cancer. Early detection and treatment can reduce the incidence of cervical cancer. AIM To investigate the detection rate of human papillomavirus (HPV) E6/E7 mRNA in cervical tissue of patients with different types of epithelial cell neoplasia (CIN) and its relationship with CIN progression and diagnosis. METHODS One hundred women with HPV infection detected by cervical exfoliation cytology between January 2022 and January 2023 were retrospectively selected. These patients were graded CIN based on colposcopy and cervical pathology. The positive expression rates of HPV E6/E7 mRNA and HPV [polymerase chain reaction (PCR)-reverse dot crossing] were compared among all groups. Patients with HPV E6/E7 mRNA expression in the grade 1 CIN group were followed up for 1 yr. The relationship between atypical squamous epithelium and high malignant epithelial neoplasia was investigated by univariate and multivariate analysis. RESULTS The diagnostic sensitivity, specificity, and sensitivity of PCR-reverse point hybridization technology for secondary CIN were 70.41%, 70.66%, and 0.714, respectively. Sensitivity and specificity for secondary CIN were 752% and 7853%, respectively, the area under the curve value was 0.789. Logistic Multifactorial model analysis revealed that the HPV positive rates and the HPV E6/E7 mRNA positive rates were independent risk factors of CIN grade I (P < 0.05). In CIN grade I patients with positive for HPV E6/E7 mRNA, in its orientation to grade CIN patients, in its orientation to grade CIN patients, at 69.2%, compared with patients negative for HPV E6/E7 mRNA (30.8%), significant difference (P < 0.05). CONCLUSION HPV E6/E7 mRNA and HPV (PCR-reverse dot hybrid) positive expression have a close relationship with CIN-grade disease progression and is an independent risk factor for high-grade CIN lesions.
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Affiliation(s)
- Ling-Li Zhang
- Department of Gynaecology, Maternal and Child Health Hospital of Hubei Province, Wuhan 430075, Hubei Province, China
| | - Ming-Yan Du
- Department of Gynaecology, China Resources WISCO General Hospital, Wuhan 430080, Hubei Province, China
| | - Xin Du
- Department of Gynaecology, Maternal and Child Health Hospital of Hubei Province, Wuhan 430075, Hubei Province, China
| | - Jie Duan
- Department of Gynaecology, Maternal and Child Health Hospital of Hubei Province, Wuhan 430075, Hubei Province, China
| | - Dong-Mei Yao
- Department of Gynaecology, Maternal and Child Health Hospital of Hubei Province, Wuhan 430075, Hubei Province, China
| | - Jing Jing
- Department of Gynaecology, Maternal and Child Health Hospital of Hubei Province, Wuhan 430075, Hubei Province, China
| | - Chun Feng
- Department of Gynaecology, Maternal and Child Health Hospital of Hubei Province, Wuhan 430075, Hubei Province, China
| | - Lin Song
- Department of Surgery, Maternal and Child Health Hospital of Hubei Province, Wuhan 430075, Hubei Province, China
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14
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Yuan W, Shi X, Lee LTO. RNA therapeutics in targeting G protein-coupled receptors: Recent advances and challenges. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102195. [PMID: 38741614 PMCID: PMC11089380 DOI: 10.1016/j.omtn.2024.102195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
G protein-coupled receptors (GPCRs) are the major targets of existing drugs for a plethora of human diseases and dominate the pharmaceutical market. However, over 50% of the GPCRs remain undruggable. To pursue a breakthrough and overcome this situation, there is significant clinical research for developing RNA-based drugs specifically targeting GPCRs, but none has been approved so far. RNA therapeutics represent a unique and promising approach to selectively targeting previously undruggable targets, including undruggable GPCRs. However, the development of RNA therapeutics faces significant challenges in areas of RNA stability and efficient in vivo delivery. This review presents an overview of the advances in RNA therapeutics and the diverse types of nanoparticle RNA delivery systems. It also describes the potential applications of GPCR-targeted RNA drugs for various human diseases.
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Affiliation(s)
- Wanjun Yuan
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa 999078, Macau, China
| | - Xiangyang Shi
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, People’s Republic of China
| | - Leo Tsz On Lee
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa 999078, Macau, China
- Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Taipa 999078, Macau, China
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15
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Mahajan M, Sarkar A, Mondal S. Cell cycle protein BORA is associated with colorectal cancer progression by AURORA-PLK1 cascades: a bioinformatics analysis. J Cell Commun Signal 2023; 17:773-791. [PMID: 36538275 PMCID: PMC10409947 DOI: 10.1007/s12079-022-00719-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed cancer in the world. A better understanding of the molecular mechanism of CRC is essential for making novel strategies for the CRC management and its prevention. The present study aims to explore the molecular mechanism through integrated bioinformatics analysis by analyzing genes and their co-expression pattern in normal and CRC states. GSE110223, GSE110224 and GSE113513 gene expression profiles were analyzed in this study. The co-expression networks for normal and tumor samples were constructed separately and analyzed to identify the modules, sub-networks and key genes. Gene regulatory network analysis was done to understand the regulatory mechanism of selected genes. Survival analysis was performed for the identified sub-networks and key genes to understand their role in CRC progression. A total of seven modules were detected and the KEGG pathway analysis revealed these modules were mainly enriched with cell cycle, metabolism and signaling-related pathways. E2F6 and ETV4 transcription factors regulating the activity of multiple genes of identified modules were found to be up-regulated in CRC. Six Sub-networks and seven key genes, BORA, CCT7, DTL, RUVBL1, RUVBL2, THEM6 and TMEM97 associated with the CRC progression were identified. Disease-gene association analysis identified a novel association of the BORA gene with CRC that activates and regulates the AURORA-PLK1 cascades in the cell cycle. Survival analysis indicates that the overexpressed BORA is associated with unfavourable overall survival in CRC. The mechanistic role of BORA in the regulation of cell cycle progression suggests that BORA might act as a potential therapeutic target for CRC.
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Affiliation(s)
- Mohita Mahajan
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, K.K. Birla Goa Campus, Zuarinagar, Goa 403726 India
| | - Angshuman Sarkar
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, K.K. Birla Goa Campus, Zuarinagar, Goa 403726 India
| | - Sukanta Mondal
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, K.K. Birla Goa Campus, Zuarinagar, Goa 403726 India
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16
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Wu J, Xia C, Liu C, Zhang Q, Xia C. The role of gut microbiota and drug interactions in the development of colorectal cancer. Front Pharmacol 2023; 14:1265136. [PMID: 37680706 PMCID: PMC10481531 DOI: 10.3389/fphar.2023.1265136] [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: 07/22/2023] [Accepted: 08/14/2023] [Indexed: 09/09/2023] Open
Abstract
The human gut microbiota is a complex ecosystem regulating the host's environmental interaction. The same functional food or drug may have varying bioavailability and distinct effects on different individuals. Drugs such as antibiotics can alter the intestinal flora, thus affecting health. However, the relationship between intestinal flora and non-antibiotic drugs is bidirectional: it is not only affected by drugs; nevertheless, it can alter the drug structure through enzymes and change the bioavailability, biological activity, or toxicity of drugs to improve their efficacy and safety. This review summarizes the roles and mechanisms of antibiotics, antihypertensive drugs, nonsteroidal anti-inflammatory drugs, lipid-lowering drugs, hypoglycemic drugs, virus-associated therapies, metabolites, and dietary in modulating the colorectal cancer gut microbiota. It provides a reference for future antitumor therapy targeting intestinal microorganisms.
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Affiliation(s)
- Jinna Wu
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Department of Pharmacy, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Cong Xia
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Can Liu
- Affiliated Foshan Maternity and Child Healthcare Hospital, Southern Medical University, Foshan, China
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Qianshi Zhang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Chenglai Xia
- Affiliated Foshan Maternity and Child Healthcare Hospital, Southern Medical University, Foshan, China
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
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17
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Hjazi A, Nasir F, Noor R, Alsalamy A, Zabibah RS, Romero-Parra RM, Ullah MI, Mustafa YF, Qasim MT, Akram SV. The pathological role of C-X-C chemokine receptor type 4 (CXCR4) in colorectal cancer (CRC) progression; special focus on molecular mechanisms and possible therapeutics. Pathol Res Pract 2023; 248:154616. [PMID: 37379710 DOI: 10.1016/j.prp.2023.154616] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/07/2023] [Accepted: 06/10/2023] [Indexed: 06/30/2023]
Abstract
Colorectal cancer (CRC) is comprised of transformed cells and non-malignant cells including cancer-associated fibroblasts (CAF), endothelial vasculature cells, and tumor-infiltrating cells. These nonmalignant cells, as well as soluble factors (e.g., cytokines), and the extracellular matrix (ECM), form the tumor microenvironment (TME). In general, the cancer cells and their surrounding TME can crosstalk by direct cell-to-cell contact and via soluble factors, such as cytokines (e.g., chemokines). TME not only promotes cancer progression through growth-promoting cytokines but also provides resistance to chemotherapy. Understanding the mechanisms of tumor growth and progression and the roles of chemokines in CRC will likely suggest new therapeutic targets. In this line, a plethora of reports has evidenced the critical role of chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12 or SDF-1) axis in CRC pathogenesis. In the current review, we take a glimpse into the role of the CXCR4/CXCL12 axis in CRC growth, metastasis, angiogenesis, drug resistance, and immune escape. Also, a summary of recent reports concerning targeting CXCR4/CXCL12 axis for CRC management and therapy has been delivered.
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Affiliation(s)
- Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | | | - Rabia Noor
- Amna Inayat Medical College, Lahore, Pakistan
| | - Ali Alsalamy
- College of Medical Technique, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | | | - Muhammad Ikram Ullah
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 75471, Aljouf, Saudi Arabia
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
| | - Maytham T Qasim
- Department of Anesthesia, College of Health and Medical Technololgy, Al-Ayen University, Thi-Qar, Iraq
| | - Shaik Vaseem Akram
- Uttaranchal Institute of Technology, Division of Research & Innovation, Uttaranchal University, Dehradun 248007, India
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18
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Alsaab HO, Almalki AH. Anti-HSP70 alleviates cell migration and proliferation in colorectal cancer cells (CRC) by targeting CXCR4 (in vitro study). Med Oncol 2023; 40:256. [PMID: 37516711 DOI: 10.1007/s12032-023-02122-6] [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: 06/05/2023] [Accepted: 07/10/2023] [Indexed: 07/31/2023]
Abstract
Colorectal cancer (CRC), the third most common cancer in men and women, accounts for 8% of new cancer cases in the US and 8 to 9% of the nation's anticipated cancer mortality in 2014. In the pathophysiology of colon cancer, heat shock protein 70 (HSP70) and CXCR4 are essential. In this research, we concentrated on the connection between CXCR4 expression and HSP70 inhibitor activity in the development of colorectal cancer. The HSP70 inhibitor's effect on cell proliferation was also evaluated. Samples were obtained from patients with CRC; the surrounding marginal tissues were considered healthy. The One CRC cell lines (HCA-7) were divided into two groups based on untreated and treated with anti-HSP70. HSP70 and CXCR4 mRNA expression and migration (Wound healing assay) were measured in these groups. Also, we evaluated the expression levels of HSP70 and CXCR4 in thirty CRC and healthy non-cancerous samples (Using Real-time PCR and Western Blotting). Moreover, we examined the viability of CRC cells in untreated and treated groups with anti-HSP70. Higher expression levels of CXCR4 (p < 0.0001) and HSP70 (p = 0.002) mRNA were observed in patients who had CRC. In contrast, lower mRNA expressions of HSP70 (p < 0.0001) and CXCR4 (P < 0.0001) were detected in the CRC cell line (HCA-7) after being treated with anti-HSP70. Moreover, the viability and migration of cancer cells were remarkably reduced in CRC cells treated with anti-HSP70. Our study's innovation was the in vitro demonstration of inhibiting HSP70 in the CRC cancer cell line drastically reduced CXCR4 expression, viability, and cancer cell migration. These findings may pave the way for additional studies on CRC cancer treatment and be examined in vivo in studies, given that the primary goal of therapy is to decrease the viability and spread of cancer cells.
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Affiliation(s)
- Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif, 21944, Saudi Arabia.
| | - Atiah H Almalki
- Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia
- Addiction and Neuroscience Research Unit, College of Pharmacy, Taif University, Al-Hawiah, Taif, 21944, Saudi Arabia
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Lucarini V, Nardozi D, Angiolini V, Benvenuto M, Focaccetti C, Carrano R, Besharat ZM, Bei R, Masuelli L. Tumor Microenvironment Remodeling in Gastrointestinal Cancer: Role of miRNAs as Biomarkers of Tumor Invasion. Biomedicines 2023; 11:1761. [PMID: 37371856 DOI: 10.3390/biomedicines11061761] [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: 05/10/2023] [Revised: 06/13/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
Gastrointestinal (GI) cancers are the most frequent neoplasm, responsible for half of all cancer-related deaths. Metastasis is the leading cause of death from GI cancer; thus, studying the processes that regulate cancer cell migration is of paramount importance for the development of new therapeutic strategies. In this review, we summarize the mechanisms adopted by cancer cells to promote cell migration and the subsequent metastasis formation by highlighting the key role that tumor microenvironment components play in deregulating cellular pathways involved in these processes. We, therefore, provide an overview of the role of different microRNAs in promoting tumor metastasis and their role as potential biomarkers for the prognosis, monitoring, and diagnosis of GI cancer patients. Finally, we relate the possible use of nutraceuticals as a new strategy for targeting numerous microRNAs and different pathways involved in GI tumor invasiveness.
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Affiliation(s)
- Valeria Lucarini
- Department of Experimental Medicine, University of Rome "Sapienza", Viale Regina Elena 324, 00161 Rome, Italy
| | - Daniela Nardozi
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
| | - Valentina Angiolini
- Department of Experimental Medicine, University of Rome "Sapienza", Viale Regina Elena 324, 00161 Rome, Italy
| | - Monica Benvenuto
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
- Departmental Faculty of Medicine and Surgery, Saint Camillus International University of Health and Medical Sciences, via di Sant'Alessandro 8, 00131 Rome, Italy
| | - Chiara Focaccetti
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
| | - Raffaele Carrano
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
| | - Zein Mersini Besharat
- Department of Experimental Medicine, University of Rome "Sapienza", Viale Regina Elena 324, 00161 Rome, Italy
| | - Roberto Bei
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
| | - Laura Masuelli
- Department of Experimental Medicine, University of Rome "Sapienza", Viale Regina Elena 324, 00161 Rome, Italy
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20
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Bocchi M, de Sousa Pereira N, de Oliveira KB, Amarante MK. Involvement of CXCL12/CXCR4 axis in colorectal cancer: a mini-review. Mol Biol Rep 2023:10.1007/s11033-023-08479-1. [PMID: 37219666 DOI: 10.1007/s11033-023-08479-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 04/19/2023] [Indexed: 05/24/2023]
Abstract
Migration of metastatic tumor cells is similar to the traffic of leukocytes and has been reported that can be guided by chemokines and their receptors, through the circulation to distant organs. The chemokine CXCL12 and its receptor CXCR4 play an essential role in hematopoietic stem cell homing and the activation of this axis supports malignant events. Binding of CXCL12 to CXCR4 activates signal transduction pathways, with broad effects on chemotaxis, cell proliferation, migration and gene expression. Thus, this axis serves as a bridge for tumor-stromal cell communication, creating a permissive microenvironment for tumor development, survival, angiogenesis and metastasis. Evidence suggests that this axis may be involved in the colorectal cancer (CRC) carcinogenesis. Therefore, we review emerging data and correlations between CXCL12/CXCR4 axis in CRC, the implications for cancer progression and possible therapeutic strategies that exploit this system.
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Affiliation(s)
- Mayara Bocchi
- Oncology Laboratory, Department of Pathology, Clinical and Toxicological Analysis, Health Sciences Center, Londrina State University, Londrina, PR, Brazil
| | - Nathália de Sousa Pereira
- Oncology Laboratory, Department of Pathology, Clinical and Toxicological Analysis, Health Sciences Center, Londrina State University, Londrina, PR, Brazil
| | - Karen Brajão de Oliveira
- Oncology Laboratory, Department of Pathology, Clinical and Toxicological Analysis, Health Sciences Center, Londrina State University, Londrina, PR, Brazil
- Department of Pathological Sciences, Biological Sciences Center, Londrina State University, Londrina, PR, Brazil
| | - Marla Karine Amarante
- Oncology Laboratory, Department of Pathology, Clinical and Toxicological Analysis, Health Sciences Center, Londrina State University, Londrina, PR, Brazil.
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21
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B7H4 Expression Is More Frequent in MSS Status Colorectal Cancer and Is Negatively Associated with Tumour Infiltrating Lymphocytes. Cells 2023; 12:cells12060861. [PMID: 36980202 PMCID: PMC10046962 DOI: 10.3390/cells12060861] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 02/22/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
The immunotherapies based on ICIs in CRC are nowadays limited to microsatellite unstable tumours which are approximately 15% of all CRC cases. There are a few new immune checkpoints belonging to the B7 family, including B7H4. B7H4 expression is associated with so-called “cold tumours”, and its function is linked to the downregulation of various immune cell populations. Our study aimed to investigate whether B7H4 expression is dependent on microsatellite status in CRC and on elucidating the immunological context in which the expression of B7H4 occurs. We enrolled 167 patients in the study. We prepared the homogenates from tumour tissues and healthy adjacent tissue to assess the B7H4 levels and the Bio-Plex Pro Human 48-cytokine panel. We assessed the microsatellite status of the tumour, B7H4 expression, CD8+ T cell population, and the TILs and budding in H + E stained slides by the IHC method. We used an online available database for further exploring the biological characteristics of B7H4. The expression of B7H4 was more frequent in microsatellite stable tumours, and was negatively associated with TILs. B7H4 is positively correlated with antitumour immunosuppressive iTME, thus contributing to the immunosuppressive environment in CRC.
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22
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Cambier S, Gouwy M, Proost P. The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention. Cell Mol Immunol 2023; 20:217-251. [PMID: 36725964 PMCID: PMC9890491 DOI: 10.1038/s41423-023-00974-6] [Citation(s) in RCA: 213] [Impact Index Per Article: 106.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 12/12/2022] [Indexed: 02/03/2023] Open
Abstract
Chemokines are an indispensable component of our immune system through the regulation of directional migration and activation of leukocytes. CXCL8 is the most potent human neutrophil-attracting chemokine and plays crucial roles in the response to infection and tissue injury. CXCL8 activity inherently depends on interaction with the human CXC chemokine receptors CXCR1 and CXCR2, the atypical chemokine receptor ACKR1, and glycosaminoglycans. Furthermore, (hetero)dimerization and tight regulation of transcription and translation, as well as post-translational modifications further fine-tune the spatial and temporal activity of CXCL8 in the context of inflammatory diseases and cancer. The CXCL8 interaction with receptors and glycosaminoglycans is therefore a promising target for therapy, as illustrated by multiple ongoing clinical trials. CXCL8-mediated neutrophil mobilization to blood is directly opposed by CXCL12, which retains leukocytes in bone marrow. CXCL12 is primarily a homeostatic chemokine that induces migration and activation of hematopoietic progenitor cells, endothelial cells, and several leukocytes through interaction with CXCR4, ACKR1, and ACKR3. Thereby, it is an essential player in the regulation of embryogenesis, hematopoiesis, and angiogenesis. However, CXCL12 can also exert inflammatory functions, as illustrated by its pivotal role in a growing list of pathologies and its synergy with CXCL8 and other chemokines to induce leukocyte chemotaxis. Here, we review the plethora of information on the CXCL8 structure, interaction with receptors and glycosaminoglycans, different levels of activity regulation, role in homeostasis and disease, and therapeutic prospects. Finally, we discuss recent research on CXCL12 biochemistry and biology and its role in pathology and pharmacology.
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Affiliation(s)
- Seppe Cambier
- Laboratory of Molecular Immunology, Rega Institute, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Mieke Gouwy
- Laboratory of Molecular Immunology, Rega Institute, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Paul Proost
- Laboratory of Molecular Immunology, Rega Institute, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
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23
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Clinical, Pathological, and Molecular Characteristics in Colorectal Cancer. Cancers (Basel) 2022; 14:cancers14235958. [PMID: 36497440 PMCID: PMC9739916 DOI: 10.3390/cancers14235958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 11/28/2022] [Accepted: 11/30/2022] [Indexed: 12/03/2022] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed cancer worldwide, and the second leading cause of death in patients with cancer [...].
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24
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Condelipes PGM, Fontes PM, Godinho-Santos A, Brás EJS, Marques V, Afonso MB, Rodrigues CMP, Chu V, Gonçalves J, Conde JP. Towards personalized antibody cancer therapy: development of a microfluidic cell culture device for antibody selection. LAB ON A CHIP 2022; 22:4717-4728. [PMID: 36349999 DOI: 10.1039/d2lc00918h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Antibody therapy has been one of the most successful therapies for a wide range of diseases, including cancer. One way of expediting antibody therapy development is through phage display technology. Here, by screening thousands of randomly assembled peptide sequences, it is possible to identify potential therapeutic candidates. Conventional screening technologies do not accommodate perfusion through the system, as is the case of standard plate-based cultures. This leads to a poor translation of the experimental results obtained in vitro when moving to a more physiologically relevant setting, such as the case of preclinical animal models or clinical trials. Microfluidics is a technology that can improve screening efficacy by replicating more physiologically relevant conditions such as shear stress. In this work, a polydimethylsiloxane/polystyrene-based microfluidic system for a continuously perfused culture of cancer cells is reported. Human colorectal adenocarcinoma cells (HCT116) expressing CXCR4 were used as a cell target. Fluorescently labeled M13 phages anti-CXCR4 were used to study the efficiency of the microfluidic system as a tool to study the binding kinetics of the engineered bacteriophages. Using our microfluidic platform, we estimated a dissociation constant of 0.45 pM for the engineered phage. Additionally, a receptor internalization assay was developed using SDF-1α to verify phage specificity to the CXCR4 receptor. Upon receptor internalization there was a signal reduction, proving that the anti-CXCR4 fluorescently labelled M13 phages bound specifically to the CXCR4 receptor. The simplicity and ease of use of the microfluidic device design presented in this work can form the basis of a generic platform that facilitates the study and optimization of therapies based on interaction with biological entities such as mammalian cells.
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Affiliation(s)
- Pedro G M Condelipes
- Instituto de Engenharia de Sistemas e Computadores - Microsistemas e Nanotecnologias (INESC MN), Lisbon, Portugal
- Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.
| | - Pedro Mendes Fontes
- Instituto de Engenharia de Sistemas e Computadores - Microsistemas e Nanotecnologias (INESC MN), Lisbon, Portugal
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Ana Godinho-Santos
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Eduardo J S Brás
- Instituto de Engenharia de Sistemas e Computadores - Microsistemas e Nanotecnologias (INESC MN), Lisbon, Portugal
- IBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Vanda Marques
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Marta B Afonso
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Cecília M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Virginia Chu
- Instituto de Engenharia de Sistemas e Computadores - Microsistemas e Nanotecnologias (INESC MN), Lisbon, Portugal
| | - João Gonçalves
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - João Pedro Conde
- Instituto de Engenharia de Sistemas e Computadores - Microsistemas e Nanotecnologias (INESC MN), Lisbon, Portugal
- Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.
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25
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Lee KC, Wu KL, Chang SF, Chang HI, Chen CN, Chen YY. Fermented Ginger Extract in Natural Deep Eutectic Solvent Enhances Cytotoxicity by Inhibiting NF-κB Mediated CXC Chemokine Receptor 4 Expression in Oxaliplatin-Resistant Human Colorectal Cancer Cells. Antioxidants (Basel) 2022; 11:2057. [PMID: 36290780 PMCID: PMC9598626 DOI: 10.3390/antiox11102057] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/08/2022] [Accepted: 10/18/2022] [Indexed: 11/21/2022] Open
Abstract
Ginger extracts have been shown to have health-promoting pharmacological activity and beneficial effects, including antioxidant and anticancer properties. The extraction of ginger by natural deep eutectic solvents (NaDES) has been shown to enhance bioactivity, but the cytotoxicity of NaDES extracts needs to be further determined. Signaling through the CXC chemokine receptor 4 (CXCR4) expressed on colorectal cancer (CRC) cells has a pivotal role in tumor cell chemosensitivity. Oxaliplatin is a third-generation platinum compound used as an effective chemotherapeutic drug for CRC treatment. However, whether ginger extract and oxaliplatin could induce a synergistic cytotoxic effect in oxaliplatin-resistant CRC cells through modulating CXCR4 expression is not known. In this study, oxaliplatin-resistant HCT-116 (HCT-116/R) cells were generated first. Ginger was extracted using the NaDES mixture betaine/lactate/water (1:2:2.5). Lactobacillus reuteri fermentation of NaDES-ginger extract increased the total polyphenol content (12.42 mg gallic acid/g in non-fermented NaDES-ginger extract and 23.66 mg gallic acid/g in fermented NaDES-ginger extract). It also increased the antioxidant activity by about 20−30% compared to non-fermented NaDES-ginger extract. In addition, it achieved low cytotoxicity to normal colonic mucosal cells and enhanced the anticancer effect on HCT-116/R cells. On the other hand, the inhibition of NF-κB activation by fermented NaDES-ginger extract significantly decreased the CXCR4 expression (p < 0.05) in HCT-116/R cells. The inactivation of NF-κB by pharmacological inhibitor pyrrolidine dithiocarbamate further enhanced the fermented NaDES-ginger extract-reduced CXCR4 expression levels (p < 0.05). Moreover, fermented NaDES-ginger extract could synergistically increase the cytotoxicity of oxaliplatin by inhibiting CXCR4 expression and inactivating NF-κB, resulting in HCT-116/R cell death. These findings demonstrate that fermented NaDES-ginger extract reduces the NF-kB-mediated activation of CXCR4 and enhances oxaliplatin-induced cytotoxicity in oxaliplatin-resistant CRC cells.
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Affiliation(s)
- Ko-Chao Lee
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Kuen-Lin Wu
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Shun-Fu Chang
- Department of Medical Research and Development, Chang Gung Memorial Hospital Chiayi Branch, Chiayi 613, Taiwan
| | - Hsin-I Chang
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan
| | - Cheng-Nan Chen
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan
| | - Yih-Yuan Chen
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan
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26
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Dai R, Tao R, Li X, Shang T, Zhao S, Ren Q. Expression profiling of mRNA and functional network analyses of genes regulated by human papilloma virus E6 and E7 proteins in HaCaT cells. Front Microbiol 2022; 13:979087. [PMID: 36188003 PMCID: PMC9515614 DOI: 10.3389/fmicb.2022.979087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/16/2022] [Indexed: 11/21/2022] Open
Abstract
Human papillomavirus (HPV) oncogenes E6 and E7 are essential for HPV-related cancer development. Here, we developed a cell line model using lentiviruses for transfection of the HPV16 oncogenes E6 and E7 and investigated the differences in mRNA expression during cell adhesion and chemokine secretion. Subsequently, RNA sequencing (RNA-seq) analysis was performed to explore the differences in mRNA expression. Compared to levels in the control group, 2,905 differentially expressed mRNAs (1,261 downregulated and 1,644 upregulated) were identified in the HaCaT-HPV16E6E7 cell line. To predict the functions of these differentially expressed genes (DEGs) the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were used. Protein–protein interactions were established, and the hub gene was identified based on this network. Real-time quantitative-PCR (RT-qPCR) was conducted to confirm the levels of 14 hub genes, which were consistent with the RNA-seq data. According to this, we found that these DEGs participate in the extracellular matrix (ECM), cell adhesion, immune control, and cancer-related signaling pathways. Currently, an increasing number of clinicians depend on E6/E7mRNA results to make a comprehensive judgment of cervical precancerous lesions. In this study, 14 hub genes closely related to the expression of cell adhesion ability and chemokines were analyzed in HPV16E6E7-stably expressing cell lines, which will open up new research ideas for targeting E6E7 in the treatment of HPV-related cancers.
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Affiliation(s)
- Renjinming Dai
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Ran Tao
- Laboratory of Clinical Applied Anatomy, Department of Human Anatomy, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Xiu Li
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Tingting Shang
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Shixian Zhao
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Qingling Ren
- The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Qingling Ren,
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27
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Novoa Díaz MB, Martín MJ, Gentili C. Tumor microenvironment involvement in colorectal cancer progression via Wnt/β-catenin pathway: Providing understanding of the complex mechanisms of chemoresistance. World J Gastroenterol 2022; 28:3027-3046. [PMID: 36051330 PMCID: PMC9331520 DOI: 10.3748/wjg.v28.i26.3027] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 04/29/2022] [Accepted: 06/20/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) continues to be one of the main causes of death from cancer because patients progress unfavorably due to resistance to current therapies. Dysregulation of the Wnt/β-catenin pathway plays a fundamental role in the genesis and progression of several types of cancer, including CRC. In many subtypes of CRC, hyperactivation of the β-catenin pathway is associated with mutations of the adenomatous polyposis coli gene. However, it can also be associated with other causes. In recent years, studies of the tumor microenvironment (TME) have demonstrated its importance in the development and progression of CRC. In this tumor nest, several cell types, structures, and biomolecules interact with neoplastic cells to pave the way for the spread of the disease. Cross-communications between tumor cells and the TME are then established primarily through paracrine factors, which trigger the activation of numerous signaling pathways. Crucial advances in the field of oncology have been made in the last decade. This Minireview aims to actualize what is known about the central role of the Wnt/β-catenin pathway in CRC chemoresistance and aggressiveness, focusing on cross-communication between CRC cells and the TME. Through this analysis, our main objective was to increase the understanding of this complex disease considering a more global context. Since many treatments for advanced CRC fail due to mechanisms involving chemoresistance, the data here exposed and analyzed are of great interest for the development of novel and effective therapies.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
| | - María Julia Martín
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
- Departamento de Química, Universidad Nacional del Sur (UNS)-INQUISUR (CONICET-UNS), Bahía Blanca 8000, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
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