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Overexpression of the miR-17-92 cluster in colorectal adenoma organoids induces a carcinoma-like genotype

ABSTRACT: Gain of chromosome arm 13q is one of the most prevalent DNA copy number alterations associated with colorectal adenoma-to-carcinoma progression. The oncogenic miR-17-92 cluster, located at 13q, was found to be overexpressed in colorectal cancer and in adenomas harboring 13q gain. However, to what extent overexpression of this group of microRNAs actually drives progression to cancer remains to be resolved. Therefore, we aimed to clarify the role of miR-17-92 cluster in the progression from colorectal adenoma to carcinoma. In human colorectal adenoma organoids without 13q gain, the miR-17-92 cluster was overexpressed and downstream effects on mRNA expression investigated, along with functional effects in vitro and in vivo. Comparison of mRNA sequencing results of organoids overexpressing miR-17-92 and cultures transduced with control vector, revealed a miR-17-92 expression signature. This signature appeared to be enriched in an independent series of colorectal cancers and adenomas tissues with 13q gain, confirming that miR-17-92 expression is associated with malignant progression. However, an increase in proliferation rate was not observed in miR-17-92 overexpressing adenoma organoids in vitro. In addition, subcutaneous injection of these organoids in immunodeficient mice was insufficient to cause tumor outgrowth. Transfecting miR-17-92 cluster in human colon adenoma organoids induces an expression signature that proved to be enriched in both adenomas with 13q gain and in colorectal cancers, supporting its role as a driver of 13q gain. However, overexpression of miR-17-92 alone is not sufficient to transform colorectal adenoma cells into a malignant phenotype.

PROVIDER: EGAS00001005949 | EGA |

REPOSITORIES: EGA

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Project description:Traditional serrated adenoma (TSA) remains the least understood of all the colorectal adenomas although these lesions have been associated with a significant cancer risk- twice that of the conventional adenoma (CAD) and of the sessile serrated adenoma (SSA/P). This study was performed to investigate the proteomic profiles of the different colorectal adenomas to better assess the pathogenesis of TSA. We performed a global quantitative expression profile of 44 colorectal adenomas (12 TSA, 15 CAD, 17 SSA/Ps) and 17 normal colonic mucosa, conserved as formalin-fixed paraffin-embedded samples, by the label-free quantification (LFQ) method. Unsupervised consensus hierarchical clustering applied to the whole proteomic profile of the 44 colorectal adenomas identified four subtypes. The C1 and C2 were well-individualized clusters composed of most of the CAD (14/15) and most of the SSA (13/17) respectively. This is consistent with the fact that CAD and SSA/Ps are homogeneous but distinct colorectal adenoma entities. In contrast, TSA were subdivided into C3 and C4 clusters that also contained CAD and SSA/Ps, consistent with the more heterogeneous entity of TSA at the morphological and molecular levels. The comparison of the proteome expression profile between the adenoma subtypes and normal colonic mucosa further confirmed the heterogeneous nature of TSA that merged either on CAD or SSA, while CAD and TSA formed homogeneous and distinct entities. Furthermore, we identified LEFTY1 a new potential marker for TSA that may be relevant for the TSA pathogenesis. LEFTY1 is an inhibitor of the Nodal/TGFb pathway that we found to be one of the most overexpressed proteins specifically in the TSA and confirmed by immunohistochemistry. Taken together, our study confirms that CAD and SSA form homogenous but distinct colorectal adenoma entities while TSA are an heterogeneous entity and may arise from either SSA or from normal mucosa that will evolve along the conventional adenoma pathway.

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Overexpression of the miR-17-92 cluster in colorectal adenoma organoids induces a carcinoma-like genotype

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