Pub Date : 2022-05-01Epub Date: 2022-04-22DOI: 10.1002/1878-0261.13214
Rafal Dziadziuszko, Tiffany Hung, Kun Wang, Voleak Choeurng, Alexander Drilon, Robert C Doebele, Fabrice Barlesi, Charlie Wu, Lucas Dennis, Joel Skoletsky, Ryan Woodhouse, Meijuan Li, Ching-Wei Chang, Brian Simmons, Todd Riehl, Timothy R Wilson
Genomic tumour profiling informs targeted treatment options. Entrectinib is a tyrosine kinase inhibitor with efficacy in NTRK fusion-positive (-fp) solid tumours and ROS1-fp non-small cell lung cancer. FoundationOne® Liquid CDx (F1L CDx), a non-invasive in vitro next-generation sequencing (NGS)-based diagnostic, detects genomic alterations in plasma circulating tumour DNA (ctDNA). We evaluated the clinical validity of F1L CDx as an aid in identifying patients with NTRK-fp or ROS1-fp tumours and assessed the genomic landscape pre- and post-entrectinib treatment. Among evaluable pre-treatment clinical samples (N = 85), positive percentage agreements between F1L CDx and clinical trial assays (CTAs) were 47.4% (NTRK fusions) and 64.5% (ROS1 fusions); positive predictive value was 100% for both. The objective response rate for CTA+ F1L CDx+ patients was 72.2% in both cohorts. The median duration of response significantly differed between F1L CDx+ and F1L CDx- samples in ROS1-fp (5.6 vs. 17.3 months) but not NTRK-fp (9.2 vs. 12.9 months) patients. Fifteen acquired resistance mutations were detected. We conclude that F1L CDx is a clinically valid complement to tissue-based testing to identify patients who may benefit from entrectinib and those with acquired resistance mutations associated with disease progression.
{"title":"Pre- and post-treatment blood-based genomic landscape of patients with ROS1 or NTRK fusion-positive solid tumours treated with entrectinib.","authors":"Rafal Dziadziuszko, Tiffany Hung, Kun Wang, Voleak Choeurng, Alexander Drilon, Robert C Doebele, Fabrice Barlesi, Charlie Wu, Lucas Dennis, Joel Skoletsky, Ryan Woodhouse, Meijuan Li, Ching-Wei Chang, Brian Simmons, Todd Riehl, Timothy R Wilson","doi":"10.1002/1878-0261.13214","DOIUrl":"10.1002/1878-0261.13214","url":null,"abstract":"<p><p>Genomic tumour profiling informs targeted treatment options. Entrectinib is a tyrosine kinase inhibitor with efficacy in NTRK fusion-positive (-fp) solid tumours and ROS1-fp non-small cell lung cancer. FoundationOne® Liquid CDx (F1L CDx), a non-invasive in vitro next-generation sequencing (NGS)-based diagnostic, detects genomic alterations in plasma circulating tumour DNA (ctDNA). We evaluated the clinical validity of F1L CDx as an aid in identifying patients with NTRK-fp or ROS1-fp tumours and assessed the genomic landscape pre- and post-entrectinib treatment. Among evaluable pre-treatment clinical samples (N = 85), positive percentage agreements between F1L CDx and clinical trial assays (CTAs) were 47.4% (NTRK fusions) and 64.5% (ROS1 fusions); positive predictive value was 100% for both. The objective response rate for CTA<sup>+</sup> F1L CDx<sup>+</sup> patients was 72.2% in both cohorts. The median duration of response significantly differed between F1L CDx<sup>+</sup> and F1L CDx<sup>-</sup> samples in ROS1-fp (5.6 vs. 17.3 months) but not NTRK-fp (9.2 vs. 12.9 months) patients. Fifteen acquired resistance mutations were detected. We conclude that F1L CDx is a clinically valid complement to tissue-based testing to identify patients who may benefit from entrectinib and those with acquired resistance mutations associated with disease progression.</p>","PeriodicalId":51134,"journal":{"name":"Molecular Oncology","volume":"16 1","pages":"2000-2014"},"PeriodicalIF":5.0,"publicationDate":"2022-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45457516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mohamad K Hammoud, Raimund Dietze, J. Pesek, F. Finkernagel, Annika Unger, Tim Bieringer, Andrea Nist, T. Stiewe, A. Bhagwat, W. Nockher, S. Reinartz, S. Müller-Brüsselbach, Johannes Graumann, R. Müller
Survival of ovarian carcinoma is associated with the abundance of immunosuppressed CD163highCD206high tumor‐associated macrophages (TAMs) and high levels of arachidonic acid (AA) in the tumor microenvironment. Here, we show that both associations are functionally linked. Transcriptional profiling revealed that high CD163 and CD206/MRC1 expression in TAMs is strongly associated with an inhibition of cytokine‐triggered signaling, mirrored by an impaired transcriptional response to interferons and IL‐6 in monocyte‐derived macrophages by AA. This inhibition of pro‐inflammatory signaling is caused by dysfunctions of the cognate receptors, indicated by the inhibition of JAK1, JAK2, STAT1, and STAT3 phosphorylation, and by the displacement of the interferon receptor IFNAR1, STAT1 and other immune‐regulatory proteins from lipid rafts. AA exposure led to a dramatic accumulation of free AA in lipid rafts, which appears to be mechanistically crucial, as the inhibition of its incorporation into phospholipids did not affect the AA‐mediated interference with STAT1 phosphorylation. Inhibition of interferon‐triggered STAT1 phosphorylation by AA was reversed by water‐soluble cholesterol, known to prevent the perturbation of lipid raft structure by AA. These findings suggest that the pharmacologic restoration of lipid raft functions in TAMs may contribute to the development new therapeutic approaches.
{"title":"Arachidonic acid, a clinically adverse mediator in the ovarian cancer microenvironment, impairs JAK‐STAT signaling in macrophages by perturbing lipid raft structures","authors":"Mohamad K Hammoud, Raimund Dietze, J. Pesek, F. Finkernagel, Annika Unger, Tim Bieringer, Andrea Nist, T. Stiewe, A. Bhagwat, W. Nockher, S. Reinartz, S. Müller-Brüsselbach, Johannes Graumann, R. Müller","doi":"10.1002/1878-0261.13221","DOIUrl":"https://doi.org/10.1002/1878-0261.13221","url":null,"abstract":"Survival of ovarian carcinoma is associated with the abundance of immunosuppressed CD163highCD206high tumor‐associated macrophages (TAMs) and high levels of arachidonic acid (AA) in the tumor microenvironment. Here, we show that both associations are functionally linked. Transcriptional profiling revealed that high CD163 and CD206/MRC1 expression in TAMs is strongly associated with an inhibition of cytokine‐triggered signaling, mirrored by an impaired transcriptional response to interferons and IL‐6 in monocyte‐derived macrophages by AA. This inhibition of pro‐inflammatory signaling is caused by dysfunctions of the cognate receptors, indicated by the inhibition of JAK1, JAK2, STAT1, and STAT3 phosphorylation, and by the displacement of the interferon receptor IFNAR1, STAT1 and other immune‐regulatory proteins from lipid rafts. AA exposure led to a dramatic accumulation of free AA in lipid rafts, which appears to be mechanistically crucial, as the inhibition of its incorporation into phospholipids did not affect the AA‐mediated interference with STAT1 phosphorylation. Inhibition of interferon‐triggered STAT1 phosphorylation by AA was reversed by water‐soluble cholesterol, known to prevent the perturbation of lipid raft structure by AA. These findings suggest that the pharmacologic restoration of lipid raft functions in TAMs may contribute to the development new therapeutic approaches.","PeriodicalId":51134,"journal":{"name":"Molecular Oncology","volume":"16 1","pages":"3146 - 3166"},"PeriodicalIF":6.6,"publicationDate":"2022-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43698325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Juliette Mainguené, S. Vacher, M. Kamal, A. Hamza, J. Masliah-Planchon, S. Baulande, Sabrina Ibadioune, E. Borcoman, W. Cacheux, V. Calugaru, L. Courtois, C. Crozes, M. Deloger, E. Girard, J. Delord, A. Dubray-Vautrin, L. Larbi Chérif, C. Dupain, E. Jeannot, J. Klijanienko, S. Lameiras, C. Lecerf, A. Modesto, A. Nicolas, R. Rouzier, E. Saâda-Bouzid, P. Saintigny, A. Sudaka, N. Servant, C. le Tourneau, I. Bièche
A prevalence of around 26% of human papillomavirus (HPV) in head and neck squamous cell carcinoma (HNSCC) has been previously reported. HPV induced oncogenesis mainly involving E6 and E7 viral oncoproteins. In some cases, HPV viral DNA has been detected to integrate with the host genome and possibly contributes to carcinogenesis by affecting the gene expression. We retrospectively assessed HPV integration sites and signatures in 80 HPV positive patients with HNSCC, by using a double capture‐HPV method followed by next‐generation Sequencing. We detected HPV16 in 90% of the analyzed cohort and confirmed five previously described mechanistic signatures of HPV integration [episomal (EPI), integrated in a truncated form revealing two HPV‐chromosomal junctions colinear (2J‐COL) or nonlinear (2J‐NL), multiple hybrid junctions clustering in a single chromosomal region (MJ‐CL) or scattered over different chromosomal regions (MJ‐SC) of the human genome]. Our results suggested that HPV remained episomal in 38.8% of the cases or was integrated/mixed in the remaining 61.2% of patients with HNSCC. We showed a lack of association of HPV genomic signatures to tumour and patient characteristics, as well as patient survival. Similar to other HPV associated cancers, low HPV copy number was associated with worse prognosis. We identified 267 HPV‐human junctions scattered on most chromosomes. Remarkably, we observed four recurrent integration regions: PDL1/PDL2/PLGRKT (8.2%), MYC/PVT1 (6.1%), MACROD2 (4.1%) and KLF5/KLF12 regions (4.1%). We detected the overexpression of PDL1 and MYC upon integration by gene expression analysis. In conclusion, we identified recurrent targeting of several cancer genes such as PDL1 and MYC upon HPV integration, suggesting a role of altered gene expression by HPV integration during HNSCC carcinogenesis.
{"title":"Human papilloma virus integration sites and genomic signatures in head and neck squamous cell carcinoma","authors":"Juliette Mainguené, S. Vacher, M. Kamal, A. Hamza, J. Masliah-Planchon, S. Baulande, Sabrina Ibadioune, E. Borcoman, W. Cacheux, V. Calugaru, L. Courtois, C. Crozes, M. Deloger, E. Girard, J. Delord, A. Dubray-Vautrin, L. Larbi Chérif, C. Dupain, E. Jeannot, J. Klijanienko, S. Lameiras, C. Lecerf, A. Modesto, A. Nicolas, R. Rouzier, E. Saâda-Bouzid, P. Saintigny, A. Sudaka, N. Servant, C. le Tourneau, I. Bièche","doi":"10.1002/1878-0261.13219","DOIUrl":"https://doi.org/10.1002/1878-0261.13219","url":null,"abstract":"A prevalence of around 26% of human papillomavirus (HPV) in head and neck squamous cell carcinoma (HNSCC) has been previously reported. HPV induced oncogenesis mainly involving E6 and E7 viral oncoproteins. In some cases, HPV viral DNA has been detected to integrate with the host genome and possibly contributes to carcinogenesis by affecting the gene expression. We retrospectively assessed HPV integration sites and signatures in 80 HPV positive patients with HNSCC, by using a double capture‐HPV method followed by next‐generation Sequencing. We detected HPV16 in 90% of the analyzed cohort and confirmed five previously described mechanistic signatures of HPV integration [episomal (EPI), integrated in a truncated form revealing two HPV‐chromosomal junctions colinear (2J‐COL) or nonlinear (2J‐NL), multiple hybrid junctions clustering in a single chromosomal region (MJ‐CL) or scattered over different chromosomal regions (MJ‐SC) of the human genome]. Our results suggested that HPV remained episomal in 38.8% of the cases or was integrated/mixed in the remaining 61.2% of patients with HNSCC. We showed a lack of association of HPV genomic signatures to tumour and patient characteristics, as well as patient survival. Similar to other HPV associated cancers, low HPV copy number was associated with worse prognosis. We identified 267 HPV‐human junctions scattered on most chromosomes. Remarkably, we observed four recurrent integration regions: PDL1/PDL2/PLGRKT (8.2%), MYC/PVT1 (6.1%), MACROD2 (4.1%) and KLF5/KLF12 regions (4.1%). We detected the overexpression of PDL1 and MYC upon integration by gene expression analysis. In conclusion, we identified recurrent targeting of several cancer genes such as PDL1 and MYC upon HPV integration, suggesting a role of altered gene expression by HPV integration during HNSCC carcinogenesis.","PeriodicalId":51134,"journal":{"name":"Molecular Oncology","volume":"16 1","pages":"3001 - 3016"},"PeriodicalIF":6.6,"publicationDate":"2022-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42530752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L. J. van Weele, Sabra I. Djomehri, S. Cai, Jane Antony, Shaheen S. Sikandar, D. Qian, W. H. D. Ho, R. West, F. Scheeren, M. Clarke
As precision medicine increases the response rate of treatment, tumors frequently bypass inhibition, and reoccur. In order for treatment to be effective long term, the mechanisms enabling treatment adaptation need to be understood. Here, we report a mouse model that, in the absence of p53 and the presence of oncogenic KrasG12D, develops breast tumors. Upon inactivation of KrasG12D, tumors initially regress and enter remission. Subsequently, the majority of tumors adapt to the withdrawal of KrasG12D expression and return. KrasG12D‐independent tumor cells show a strong mesenchymal profile with active RAS‐RAF‐MEK‐ERK (MAPK/ERK) signaling. Both KrasG12D‐dependent and KrasG12D‐independent tumors display a high level of genomic instability, and KrasG12D‐independent tumors harbor numerous amplified genes that can activate the MAPK/ERK signaling pathway. Our study identifies both epithelial‐mesenchymal transition (EMT) and active MAPK/ERK signaling in tumors that adapt to oncogenic KrasG12D withdrawal in a novel Trp53−/− breast cancer mouse model. To achieve long‐lasting responses in the clinic to RAS‐fueled cancer, treatment will need to focus in parallel on obstructing tumors from adapting to oncogene inhibition.
{"title":"Mesenchymal tumor cells drive adaptive resistance of Trp53−/− breast tumor cells to inactivated mutant Kras","authors":"L. J. van Weele, Sabra I. Djomehri, S. Cai, Jane Antony, Shaheen S. Sikandar, D. Qian, W. H. D. Ho, R. West, F. Scheeren, M. Clarke","doi":"10.1002/1878-0261.13220","DOIUrl":"https://doi.org/10.1002/1878-0261.13220","url":null,"abstract":"As precision medicine increases the response rate of treatment, tumors frequently bypass inhibition, and reoccur. In order for treatment to be effective long term, the mechanisms enabling treatment adaptation need to be understood. Here, we report a mouse model that, in the absence of p53 and the presence of oncogenic KrasG12D, develops breast tumors. Upon inactivation of KrasG12D, tumors initially regress and enter remission. Subsequently, the majority of tumors adapt to the withdrawal of KrasG12D expression and return. KrasG12D‐independent tumor cells show a strong mesenchymal profile with active RAS‐RAF‐MEK‐ERK (MAPK/ERK) signaling. Both KrasG12D‐dependent and KrasG12D‐independent tumors display a high level of genomic instability, and KrasG12D‐independent tumors harbor numerous amplified genes that can activate the MAPK/ERK signaling pathway. Our study identifies both epithelial‐mesenchymal transition (EMT) and active MAPK/ERK signaling in tumors that adapt to oncogenic KrasG12D withdrawal in a novel Trp53−/− breast cancer mouse model. To achieve long‐lasting responses in the clinic to RAS‐fueled cancer, treatment will need to focus in parallel on obstructing tumors from adapting to oncogene inhibition.","PeriodicalId":51134,"journal":{"name":"Molecular Oncology","volume":"16 1","pages":"3128 - 3145"},"PeriodicalIF":6.6,"publicationDate":"2022-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46636209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-04-01Epub Date: 2022-03-15DOI: 10.1002/1878-0261.13206
Yuan Peng, Yonghong Chen, Mengmeng Song, Xiaoyue Zhang, Pansong Li, Xian Yu, Yusheng Huang, Ni Zhang, Liyan Ji, Lei Xia, Xuefeng Xia, Xin Yi, Benxu Tan, Zhenzhou Yang
Homozygous deletion (HD) of CDKN2A and CDKN2B (CDKN2A/BHD ) is the most frequent copy-number variation (CNV) in lung adenocarcinoma (LUAD). CDKN2A/BHD has been associated with poor outcomes in LUAD; however, the mechanisms of its prognostic effect remain unknown. We analyzed genome, transcriptome, and clinical data from 517 patients with LUAD from the Cancer Genome Atlas (TCGA) and from 788 primary LUAD tumor and matched control samples from the MSK-IMPACT clinical cohort. CDKN2A/BHD was present in 19.1% of the TCGA-LUAD cohort and in 5.7% of the MSK-IMPACT cohort. CDKN2A/BHD patients had shorter disease-free survival and overall survival compared with CDKN2A/BWT individuals in both cohorts. Differences in clinical features did not influence the outcomes in the CDKN2A/BHD population. Mutation analyses showed that overall tumor mutational burden and mutations in classical drivers such as EGFR and RB1 were not associated with CDKN2A/BHD . In contrast, homozygous deletion of type I interferons (IFN-IHD ) frequently co-occurred with CDKN2A/BHD . CDKN2A/B and IFN-I are co-located in the same p21.3 region of chromosome 9. The co-occurrence of CDKN2A/BHD and IFN-IHD was not related to whole-genome doubling, chromosome instability, or aneuploidy. Patients with co-occurring CDKN2A/BHD and IFN-IHD had shorter disease-free survival and overall survival compared with CDKN2A/BWT patients. CDKN2A/BHD IFN-IHD had downregulated several key immune response pathways, suggesting that poor prognosis in CDKN2A/BHD LUAD could potentially be attributed to an immunosuppressive tumor microenvironment as a result of IFN-I depletion.
{"title":"Co-occurrence of CDKN2A/B and IFN-I homozygous deletions correlates with an immunosuppressive phenotype and poor prognosis in lung adenocarcinoma.","authors":"Yuan Peng, Yonghong Chen, Mengmeng Song, Xiaoyue Zhang, Pansong Li, Xian Yu, Yusheng Huang, Ni Zhang, Liyan Ji, Lei Xia, Xuefeng Xia, Xin Yi, Benxu Tan, Zhenzhou Yang","doi":"10.1002/1878-0261.13206","DOIUrl":"10.1002/1878-0261.13206","url":null,"abstract":"<p><p>Homozygous deletion (HD) of CDKN2A and CDKN2B (CDKN2A/B<sup>HD</sup> ) is the most frequent copy-number variation (CNV) in lung adenocarcinoma (LUAD). CDKN2A/B<sup>HD</sup> has been associated with poor outcomes in LUAD; however, the mechanisms of its prognostic effect remain unknown. We analyzed genome, transcriptome, and clinical data from 517 patients with LUAD from the Cancer Genome Atlas (TCGA) and from 788 primary LUAD tumor and matched control samples from the MSK-IMPACT clinical cohort. CDKN2A/B<sup>HD</sup> was present in 19.1% of the TCGA-LUAD cohort and in 5.7% of the MSK-IMPACT cohort. CDKN2A/B<sup>HD</sup> patients had shorter disease-free survival and overall survival compared with CDKN2A/B<sup>WT</sup> individuals in both cohorts. Differences in clinical features did not influence the outcomes in the CDKN2A/B<sup>HD</sup> population. Mutation analyses showed that overall tumor mutational burden and mutations in classical drivers such as EGFR and RB1 were not associated with CDKN2A/B<sup>HD</sup> . In contrast, homozygous deletion of type I interferons (IFN-I<sup>HD</sup> ) frequently co-occurred with CDKN2A/B<sup>HD</sup> . CDKN2A/B and IFN-I are co-located in the same p21.3 region of chromosome 9. The co-occurrence of CDKN2A/B<sup>HD</sup> and IFN-I<sup>HD</sup> was not related to whole-genome doubling, chromosome instability, or aneuploidy. Patients with co-occurring CDKN2A/B<sup>HD</sup> and IFN-I<sup>HD</sup> had shorter disease-free survival and overall survival compared with CDKN2A/B<sup>WT</sup> patients. CDKN2A/B<sup>HD</sup> IFN-I<sup>HD</sup> had downregulated several key immune response pathways, suggesting that poor prognosis in CDKN2A/B<sup>HD</sup> LUAD could potentially be attributed to an immunosuppressive tumor microenvironment as a result of IFN-I depletion.</p>","PeriodicalId":51134,"journal":{"name":"Molecular Oncology","volume":"16 1","pages":"1746-1760"},"PeriodicalIF":5.0,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9019898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46133462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shuai Wu, Wei Yuan, Wei-Wei Luo, K. Nie, Xing Wu, Xiangrui Meng, Zhaohua Shen, Xiaoyan Wang
Inflammatory bowel disease, characterised by chronic relapsing‐remitting colitis, is a significant risk factor for colorectal cancer (CRC). Previously, we showed that miR‐126 functions as a tumour suppressor in CRC and is inversely correlated with tumour proliferation, metastasis and patient prognosis. In the current study, we documented a protective role for miR‐126 in colitis‐associated CRC (CAC) and its underlying mechanism. We detected downregulated miR‐126 expression during colorectal tumorigenesis in the mouse CAC model and in specimens from patients with CRC. The deficiency of miR‐126 in intestinal epithelial cells (IECs) exacerbated tumorigenesis in mice. We identified CXCL12 as a direct target of miR‐126 in inhibiting the development of colitis and CAC. Moreover, miR‐126 regulated the recruitment of macrophages via CXCL12 and decreased the levels of proinflammatory cytokines (IL‐6, IL‐12 and IL‐23). In addition, IL‐6 secreted by macrophages, which were regulated by cocultured transfected CRC cells, altered the proliferation and migration of colon cells. Our data suggest that miR‐126 exerts an antitumour effect on CAC by regulating the crosstalk between IECs and macrophages via CXCL12‐IL‐6 signalling. Our study contributes to the understanding of cancer progression and suggests miR‐126 as a potential therapy for CRC.
{"title":"miR‐126 downregulates CXCL12 expression in intestinal epithelial cells to suppress the recruitment and function of macrophages and tumorigenesis in a murine model of colitis‐associated colorectal cancer","authors":"Shuai Wu, Wei Yuan, Wei-Wei Luo, K. Nie, Xing Wu, Xiangrui Meng, Zhaohua Shen, Xiaoyan Wang","doi":"10.1002/1878-0261.13218","DOIUrl":"https://doi.org/10.1002/1878-0261.13218","url":null,"abstract":"Inflammatory bowel disease, characterised by chronic relapsing‐remitting colitis, is a significant risk factor for colorectal cancer (CRC). Previously, we showed that miR‐126 functions as a tumour suppressor in CRC and is inversely correlated with tumour proliferation, metastasis and patient prognosis. In the current study, we documented a protective role for miR‐126 in colitis‐associated CRC (CAC) and its underlying mechanism. We detected downregulated miR‐126 expression during colorectal tumorigenesis in the mouse CAC model and in specimens from patients with CRC. The deficiency of miR‐126 in intestinal epithelial cells (IECs) exacerbated tumorigenesis in mice. We identified CXCL12 as a direct target of miR‐126 in inhibiting the development of colitis and CAC. Moreover, miR‐126 regulated the recruitment of macrophages via CXCL12 and decreased the levels of proinflammatory cytokines (IL‐6, IL‐12 and IL‐23). In addition, IL‐6 secreted by macrophages, which were regulated by cocultured transfected CRC cells, altered the proliferation and migration of colon cells. Our data suggest that miR‐126 exerts an antitumour effect on CAC by regulating the crosstalk between IECs and macrophages via CXCL12‐IL‐6 signalling. Our study contributes to the understanding of cancer progression and suggests miR‐126 as a potential therapy for CRC.","PeriodicalId":51134,"journal":{"name":"Molecular Oncology","volume":"16 1","pages":"3465 - 3489"},"PeriodicalIF":6.6,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44833954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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