المؤلفون: Yuquan Wei, Zhao Huang, Zong-Guang Zhou, Jingwen Jiang, Jiayang Liu, Yan Chen, Hai-Ning Chen, Canhua Huang, Qin Ye, Maochao Luo, Ke Xie, Siyuan Qin, Na Xie, Zhe Zhang

المصدر: Oncogene. 40:3394-3407

مصطلحات موضوعية: Male, 0301 basic medicine, Cancer Research, Stromal cell, Colorectal cancer, Kruppel-Like Transcription Factors, Mice, Nude, Biology, Metastasis, Mice, 03 medical and health sciences, 0302 clinical medicine, Cancer-Associated Fibroblasts, Downregulation and upregulation, Cell Movement, Transforming Growth Factor beta, Cell Line, Tumor, Tumor Microenvironment, Genetics, Transcriptional regulation, medicine, Animals, Humans, Neoplasm Metastasis, Fibroblast, neoplasms, Molecular Biology, Mice, Inbred BALB C, Tumor microenvironment, Serine Endopeptidases, Membrane Proteins, medicine.disease, digestive system diseases, Survival Rate, ADAM Proteins, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Disease Progression, Cancer research, Heterografts, Colorectal Neoplasms, Transforming growth factor

الوصف: Poorly differentiated colorectal cancer (CRC) is characterized by aggressive invasion and stromal fibroblast activation, which results in rapid progression and poor therapeutic consequences. However, the regulatory mechanism involved remains unclear. Here, we showed that ZNF37A, a member of KRAB-ZFP family, was upregulated in poorly differentiated CRCs and associated with tumor metastasis. ZNF37A enhanced the metastatic potential of multiple CRC cell lines and promoted distant metastasis in an orthotopic CRC model. Further investigation attributed the ZNF37A-exacerbated metastasis to increased extracellular TGF-β and the consequent activation of cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME). Mechanistically, ZNF37A formed a complex with KAP1 and bound to the promoter of THSD4, a TME modulator, to suppress its transcription, which is required for ZNF37A-mediated TGF-β activation and CRC metastasis. Collectively, our study indicates that ZNF37A promotes TGF-β signaling in CRC cells and activates CAFs by transcriptionally repressing THSD4 to drive CRC metastasis, implicating ZNF37A as a potential biomarker for CRC differentiation and progression.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9bf31f8f1a0176f6bd72bed75663d3c3Test
https://doi.org/10.1038/s41388-021-01713-9Test

المؤلفون: Xuyang Xia, Lunzhi Dai, Yong Peng, Han Luo, Canhua Huang, Maochao Luo, Hongying Zhang, Yang Shu, Hongbo Hu, Zong-Guang Zhou, Yuan Li, Fei Liao, Heng Xu, Minyuan Cao, Xue Liao, Yun Qin, Bo Liu, Li Yang, Wei-Han Zhang, Qiu-Luo Liu, Qianqian Hou, Wei Cheng, Zhinan Xue, Biao Dong, Yuquan Wei, Yan Zhang, Hai-Ning Chen, Wei Zhang, Lie Yang, Xianghui Fu, Zhu Wang, Shouyue Zhang, Jiankun Hu

المصدر: Gut

مصطلحات موضوعية: 0301 basic medicine, China, Lung Neoplasms, Colorectal cancer, Colon, colorectal cancer, Biology, Gene mutation, Metastasis, Cohort Studies, Evolution, Molecular, 03 medical and health sciences, 0302 clinical medicine, colorectal metastases, Biopsy, Exome Sequencing, medicine, CRISPR, Humans, gene mutation, Gene, Lung, medicine.diagnostic_test, Models, Genetic, Liver Neoplasms, Gastroenterology, Cancer, medicine.disease, digestive system diseases, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Mutation, Cancer research, Colorectal Neoplasms, Transcription Factors

الوصف: ObjectiveThe systemic spread of colorectal cancer (CRC) is dominated by the portal system and exhibits diverse patterns of metastasis without systematical genomic investigation. Here, we evaluated the genomic evolution of CRC with multiorgan metastases using multiregion sequencing.DesignWhole-exome sequencing was performed on multiple regions (n=74) of matched primary tumour, adjacent non-cancerous mucosa, liver metastasis and lung metastasis from six patients with CRC. Phylogenetic reconstruction and evolutionary analyses were used to investigate the metastatic seeding pattern and clonal origin. Recurrent driver gene mutations were analysed across patients and validated in two independent cohorts. Metastatic assays were performed to examine the effect of the novel driver gene on the malignant behaviour of CRC cells.ResultsBased on the migration patterns and clonal origins, three models were revealed (sequential, branch-off and diaspora), which not only supported the anatomic assumption that CRC cells spread to lung after clonally expanding in the liver, but also illustrated the direct seeding of extrahepatic metastases from primary tumours independently. Unlike other cancer types, polyphyletic seeding occurs in CRC, which may result in late metastases with intermetastatic driver gene heterogeneity. In cases with rapid dissemination, we found recurrent trunk loss-of-function mutations in ZFP36L2, which is enriched in metastatic CRC and associated with poor overall survival. CRISPR/Cas9-mediated knockout of ZFP36L2 enhances the metastatic potential of CRC cells.ConclusionOur results provide genomic evidence for metastatic evolution and indicate that biopsy/sequencing of metastases may be considered for patients with CRC with multiorgan or late postoperative metastasis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::204a3a563d60911dcf9f169dea0e551cTest
http://europepmc.org/articles/PMC8762014Test

المؤلفون: Edouard C. Nice, Li Zhou, Wei Gao, Changlong Li, Yujia He, Junhong Han, Yunlong Lei, Zhe Zhang, Lu Zhang, Hai-Ning Chen, Xiawei Wei, Canhua Huang, Siyuan Qin, Zong-Guang Zhou, Jiayang Liu, Yan Chen

المصدر: Theranostics

مصطلحات موضوعية: 0301 basic medicine, Receptors, Steroid, ER-phagy, Brigatinib, Colorectal cancer, Medicine (miscellaneous), Mice, Nude, Antineoplastic Agents, Apoptosis, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Organophosphorus Compounds, hemic and lymphatic diseases, Endopeptidases, medicine, Autophagy, Anaplastic lymphoma kinase, Animals, Humans, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), Protein Kinase Inhibitors, Mice, Inbred BALB C, business.industry, Ubiquitination, ALK independence, medicine.disease, Endoplasmic Reticulum Stress, HCT116 Cells, 030104 developmental biology, Pyrimidines, chemistry, A549 Cells, 030220 oncology & carcinogenesis, Cancer cell, Unfolded protein response, Cancer research, Female, Growth inhibition, business, ER stress, Colorectal Neoplasms, HT29 Cells, Research Paper

الوصف: Rationale: The sustained and severe endoplasmic reticulum (ER) stress in cancer cells may contribute to apoptotic cell death, thus representing a potential target for cancer therapy. Brigatinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small-cell lung cancer (NSCLC). However, it remains unclear if brigatinib has alternative model of action to exert antitumor effect in ALK-negative cancers. Methods: ALK-positive NSCLC cells and various human ALK-negative cancer cells, especially human colorectal cancer (CRC) cells were used to examine the tumor suppression effect of brigatinib alone or in combination with autophagy inhibitors in vitro and in vivo. A variety of biochemical assays were conducted to elucidate the underlying mechanisms of brigatinib in CRC cells. Results: Here, we show the significant anti-cancer effect of brigatinib in CRC through induction of apoptosis by sustained ER stress. Mechanistically, brigatinib induces ER stress via promoting the interaction between ubiquitin-specific peptidase 5 (USP5), a deubiquitinase, and oxysterol-binding protein-related protein 8 (ORP8), leading to ORP8 deubiquitination, accumulation and growth inhibition. Furthermore, we find that brigatinib-mediated ER stress simultaneously induces autophagic response via ER-phagy that acts as a protective mechanism to relieve excessive ER stress. As such, combination of brigatinib with autophagy inhibitors significantly enhances the anti-CRC effect of brigatinib both in vitro and in vivo, supporting the repurposing of brigatinib in CRC, independently of ALK. Conclusion: The unearthed new molecular action of brigatinib suggests that therapeutic modulation of ER stress and autophagy might represent a valid strategy to treat CRC and perhaps other ALK-negative cancers.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7567f868c25936eeaa2869c2e478b087Test
http://europepmc.org/articles/PMC6691391Test

المؤلفون: Hai-Ning Chen, Li-Bin Huang, Ting-Han Yang

المصدر: Gastroenterology. 161:732-733

مصطلحات موضوعية: Hepatology, Tumor budding, business.industry, Colorectal cancer, Gastroenterology, Cancer research, Medicine, Lymph node metastasis, business, medicine.disease

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::90b0a2f5ba1144839bf6e23a46cf7620Test
https://doi.org/10.1053/j.gastro.2020.12.053Test

المؤلفون: Canhua Huang, Xingyue Yang, Hai-Ning Chen, Maochao Luo, Edouard C. Nice

المصدر: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1876:188623

مصطلحات موضوعية: Cancer Research, Colorectal cancer, Drug resistance, Epigenesis, Genetic, Histones, Genetics, Humans, Medicine, Epigenetics, neoplasms, Gene, biology, business.industry, DNA Methylation, medicine.disease, Non-coding RNA, digestive system diseases, Histone, Oncology, Drug Resistance, Neoplasm, DNA methylation, Cancer research, biology.protein, Colorectal Neoplasms, business, Epigenetic therapy, Signal Transduction

الوصف: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Despite significant progress that has been made in therapies against CRC over the past decades, drug resistance is still a major limitation in CRC treatment. Numerous investigations have unequivocally shown that epigenetic regulation plays an important role in CRC drug resistance because of the high rate of epigenetic alterations in multiple genes during cancer development or drug treatment. Furthermore, the reversibility of epigenetic alterations provides novel therapeutic strategies to overcome drug resistance using small molecules, which can target non-coding RNAs or reverse histone modification and DNA methylation. In this review, we discuss epigenetic regulation in CRC drug resistance and the possible role of preventing or reversing CRC drug resistance using epigenetic therapy in CRC treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::921db992c5d63154f9e181f7ab2f0bb5Test
https://doi.org/10.1016/j.bbcan.2021.188623Test

المؤلفون: Edouard C. Nice, Kefei Yuan, Canhua Huang, Yan Chen, Zhao Huang, Hai-Ning Chen, Na Xie, Min Wu, Qianhui Dou, Kui Wang, Zong-Guang Zhou

المصدر: Cancer Research. 76:1122-1134

مصطلحات موضوعية: Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Epithelial-Mesenchymal Transition, Beta-catenin, Colorectal cancer, Mouse model of colorectal and intestinal cancer, Biology, Metastasis, Mice, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Cell Line, Tumor, Internal medicine, medicine, Animals, Humans, Neoplasm Invasiveness, Epithelial–mesenchymal transition, Promoter Regions, Genetic, beta Catenin, Mice, Inbred BALB C, Protein Stability, Cadherin, Liver Neoplasms, DNA Methylation, LIM Domain Proteins, Cadherins, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Catenin complex, Colorectal Neoplasms, Protein Binding, Transcription Factors

الوصف: Metastasis is a major cause of death in patients with colorectal cancer, and increasing evidence supports the contribution of the epithelial–mesenchymal transition (EMT) to cancer progression. The dissociation of the E-cadherin/β-catenin adhesion complex represents a key step in EMT and promotes cancer invasion and metastasis, but the upstream signaling pathways regulating this interaction are poorly understood. Here, we show that PDLIM1, a member of the PDZ and LIM protein family, was downregulated in highly metastatic colorectal cancer cells and liver metastases from colorectal cancer patients. We found that loss of PDLIM1 promoted the expression of EMT markers and increased the invasive and migratory properties of multiple colorectal cancer cell lines. Furthermore, PDLIM1 knockdown increased colon-derived liver metastasis in an orthotopic colorectal cancer model and promoted distant metastatic colonization in an experimental lung metastasis model. Mechanistic investigations revealed that PDLIM1 interacted with and stabilized the E-cadherin/β-catenin complex, thereby inhibiting the transcriptional activity of β-catenin and preventing EMT. Accordingly, PDLIM1 overexpression attenuated EMT of colorectal cancer cells. Moreover, the downregulation of PDLIM1 in colorectal cancer samples correlated with reduced E-cadherin and membrane β-catenin levels, and was associated with shorter overall survival. In conclusion, our study demonstrates that PDLIM1 suppresses EMT and metastatic potential of colorectal cancer cells by stabilizing β-catenin at cell–cell junctions, and its loss in metastatic tissues may represent a potential prognostic marker of aggressive disease. Cancer Res; 76(5); 1122–34. ©2015 AACR.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::24740f67ab822a5f5cb2113b1f6ac939Test
https://doi.org/10.1158/0008-5472.can-15-1962Test

المؤلفون: Hai-Ning Chen, Bo Zhang, Zong-Guang Zhou, Zhi-Xin Chen, Jia-Ping Chen, Xin-Zu Chen, Chen Yang, Jiankun Hu, Kun Yang

المصدر: The International journal of biological markers. 26(3)

مصطلحات موضوعية: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, Clinical Biochemistry, In Vitro Techniques, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Antigen, Cancer stem cell, Antigens, CD, Internal medicine, medicine, Humans, AC133 Antigen, Glycoproteins, business.industry, Brain Neoplasms, Absolute risk reduction, medicine.disease, In vitro, 030104 developmental biology, Cell culture, 030220 oncology & carcinogenesis, Meta-analysis, Neoplastic Stem Cells, Biomarker (medicine), business, Colorectal Neoplasms, Peptides

الوصف: Background CD133 has been used to identify normal and cancer stem cells from several different tissues. Nowadays some researchers have reported that CD133 expression was not restricted to cancer stem cells (CSCs) of colorectal cancer and brain tumors, and CD133-negative subsets could also initiate tumors. We therefore performed a meta-analysis to assess the value of CD133 as a biomarker of CSCs for colorectal cancer and brain tumors. Methods A Medline search was performed to identify relevant studies for the analysis. The meta-analysis was done using RevMan 5.0 software. Outcome measures were colony formation rate and xenotransplanted tumor formation rate. Results Fifteen identified studies were available for analysis. For in vitro tests, there were no significant differences in the colony formation rates between CD133-positive and CD133-negative cells for colorectal cancer and brain tumors. For in vivo tests, the xenotransplanted tumor formation rate showed a significant difference between CD133-positive cells and CD133-negative cells in colorectal cancer only, corresponding to a risk difference of 0.40 (95%CI: 0.07, 0.73). Samples (cell lines versus tissues), applied biomarkers (combined versus single), and injection site were included as factors in sensitivity analyses, but the results were very inconsistent. Conclusions CD133 may not be suitable as a universe biomarker in identifying CSCs of colorectal cancer and brain tumors. Additional studies are necessary to further delineate its role.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3ce6d198397a7e5d95f954d9e907a8eeTest
https://pubmed.ncbi.nlm.nih.gov/21786247Test