Novel evidence for an oncogenic role of microRNA-21 in colitis-associated colorectal cancer

Shi, Chenzhang; Yang, Yongzhi; Xia, Yang; Okugawa, Yoshinaga; Yang, Jun; Liang, Yong; Chen, Hongqi; Zhang, Peng; Feng, Wenquan; Han, Huazhong; Wu, Wen; Gao, Renyuan; Gasché, Christoph; Qin, Huanlong; Ma, Yanlei; Goel, Ajay

doi:10.1136/gutjnl-2014-308455

Cited by 129 publications

(102 citation statements)

References 48 publications

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“…Following AOM and DSS intervention, miR-21-knockout mice showed a decrease in the size and number of tumours compared with the control group. The absence of miR-21 also reduced the expression of inflammatory cytokines (IL-6, IL-23, IL-17A and IL-21) and attenuated the proliferation of tumour cells [44]. All of these reports support our results indirectly.…”

Section: Discussionsupporting

confidence: 87%

Long non-coding RNA growth arrest specific transcript 5 acts as a tumour suppressor in colorectal cancer by inhibiting interleukin-10 and vascular endothelial growth factor expression

Huang

et al. 2017

Oncotarget

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Long non-coding RNAs (lncRNAs) are highly involved in diverse biological processes of human malignancies. The expression profile and underlying mechanism of lncRNA growth arrest specific transcript 5 (GAS5) in colorectal cancer (CRC) is poorly understood. In this study, we found that GAS5 was commonly downregulated in CRC tissues, serum of CRC patients and CRC cell lines. Knockdown of GAS5 promoted CRC cell proliferation and colony formation, whereas overexpression of GAS5 produced the opposite result. We further demonstrated that knockdown of GAS5 increased the expression and secretion of interleukin-10 (IL-10) and vascular endothelial growth factor (VEGF-A) via NF-κB and Erk1/2 pathways. Neutralization of IL-10 and VEGF-A reduced tumour proli feration caused by GAS5 knockdown. Moreover, GAS5 expression showed a statistically significant correlation with the mRNA levels of IL-10 and VEGF-A in CRC tissues. We further illustrated that GAS5 was markedly downregulated and negatively correlated with the cytokine expression in a mouse model of colitis-associated cancer (CAC). These results delineate a novel mechanism of lncRNA GAS5 in suppressing colorectal carcinogenesis. The cytokines IL-10 and VEGF-A inhibited by GAS5 may provide targets for lncRNA-based therapies for CRC.

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Section: Discussionsupporting

confidence: 87%

Long non-coding RNA growth arrest specific transcript 5 acts as a tumour suppressor in colorectal cancer by inhibiting interleukin-10 and vascular endothelial growth factor expression

Huang

et al. 2017

Oncotarget

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“…Accumulating evidence indicates that inflammatory responses can alter expression of microRNAs, some of which may contribute to tumor progression (11, 12). Among those microRNAs, MIR21 (miR-21) has been shown to promote inflammation-associated colorectal tumorigenesis in animal models (13, 14). In addition, studies of human colorectal cancer tissue have shown that MIR21 is upregulated in colorectal cancer cells, and that tumor MIR21 expression level is associated with high-level expression of the genes involved in inflammatory responses and worse clinical outcome (15, 16).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA MIR21 (miR-21) and PTGS2 Expression in Colorectal Cancer and Patient Survival

Mima

Nishihara

Yang

et al. 2016

Clinical Cancer Research

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Purpose Prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase-2; a target of aspirin) produces inflammatory mediator prostaglandin E2 (PGE2), and contributes to colorectal neoplasia development. PTGS2-driven inflammatory responses can induce tumor expression of microRNA MIR21 (miR-21) that can increase local PGE2 level by downregulating PGE2-metabolizing enzymes. We hypothesized that the prognostic association of tumor MIR21 expression level in colorectal carcinoma might depend on inflammatory tumor microenvironment and be stronger in tumors expressing high-level PTGS2. Experimental Design Utilizing 765 rectal and colon cancer specimens in the Nurses’ Health Study and the Health Professionals Follow-up Study, we measured MIR21 expression by quantitative reverse-transcription PCR, and PTGS2 expression by immunohistochemistry. Cox proportional hazards regression model was used to assess statistical interaction between MIR21 and PTGS2 in colorectal cancer-specific survival analysis, controlling for potential confounders including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation level, and KRAS, BRAF, and PIK3CA mutations. Results Tumor MIR21 expression level was associated with higher colorectal cancer-specific mortality (Ptrend = 0.029), and there was a statistically significant interaction between MIR21 and PTGS2 (Pinteraction = 0.0004). The association between MIR21 expression and colorectal cancer-specific mortality was statistically significant in PTGS2-high cancers (multivariable hazard ratio of the highest vs. lowest quartile of MIR21, 2.28; 95% confidence interval, 1.42 to 3.67; Ptrend = 0.0004) but not in PTGS2-absent/low cancers (Ptrend = 0.22). Conclusions MIR21 expression level in colorectal carcinoma is associated with worse clinical outcome, and this association is stronger in carcinomas expressing high-level PTGS2, suggesting complex roles of immunity and inflammation in tumor progression.

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“…The mechanism through which chronic inflammation results in CRC is felt to be through the induction of cytokines and chemokines, with ensuing alterations in epithelial cell proliferation, survival, and migration. (32–42) (Figure 1) In contrast to sporadic CRC, which is postulated to develop from 1 or 2 foci of dysplasia, colitis associated CRC is hypothesized to develop from multifocal dysplasia where the inflamed colonic mucosa undergoes a field change of cancer-associated molecular alterations before there is any histologic evidence of dysplasia. (2, 24, 43–45) Broadly, two of the most common somatic genetic abnormalities identified in CRC are chromosomal instability (CIN) and microsatellite instability (MSI).…”

Section: Pathogenesismentioning

confidence: 99%

Colorectal Cancer and Dysplasia in Inflammatory Bowel Disease: A Review of Disease Epidemiology, Pathophysiology, and Management

Dulai

Sandborn

Gupta

2016

Cancer Prevention Research

153

108

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Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) characterized by recurrent episodes of mucosal inflammation. This chronic mucosal inflammation has several potential consequences, one of which is the occurrence of colitis associated colorectal cancer (CRC). Over the past decade our understanding of the epidemiology, pathophysiology, and overall approach to diagnosing and managing colitis associated CRC, has grown considerably. In the current review article, we outline these advancements and highlight areas in need of further research.

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Novel evidence for an oncogenic role of microRNA-21 in colitis-associated colorectal cancer

Abstract: These observations provide novel evidence for miR-21 blockade to be a key strategy in reducing CAC.

Cited by 129 publications

References 48 publications

Long non-coding RNA growth arrest specific transcript 5 acts as a tumour suppressor in colorectal cancer by inhibiting interleukin-10 and vascular endothelial growth factor expression

Long non-coding RNA growth arrest specific transcript 5 acts as a tumour suppressor in colorectal cancer by inhibiting interleukin-10 and vascular endothelial growth factor expression

MicroRNA MIR21 (miR-21) and PTGS2 Expression in Colorectal Cancer and Patient Survival

Colorectal Cancer and Dysplasia in Inflammatory Bowel Disease: A Review of Disease Epidemiology, Pathophysiology, and Management

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