miR-450b-5p induced by oncogenic KRAS is required for colorectal cancer progression

Abstract

The development and progression of CRC are regarded as a complicated network and progressive event including genetic and/or epigenetic alterations. Recent researches revealed that MicroRNAs are biomarkers and regulators of CRC progression. Analyses of published microarray datasets revealed that miR-450b-5p was highly up-regulated in CRC tissues. In addition, high expression of miR-450b-5p was significantly associated with KRAS mutation. However, the role of miR-450b-5p in the progression of CRC remains unknown. Here, we sought to validate the expression of miR-450b-5p in CRC tissues and investigate the role and underlying mechanism of miR-450b-5p in the progression of CRC. The results revealed that miR-450b-5p was up-regulated in CRC tissues, high expression level of miR-450b-5p was positively associated with poor differentiation, advanced TNM classification and poor prognosis. Moreover, miR-450b-5p was especially high in KRAS-mutated cell lines and could be up-regulated by KRAS/AP-1 signaling. Functional validation revealed that overexpression of miR-450b-5p promoted cell proliferation and tumor growth while inhibited apoptosis of CRC cells. Furthermore, we demonstrated that miR-450b-5p directly bound the 3′-UTRs of SFRP2 and SIAH1, and activated Wnt/β-Catenin signaling. In conclusion, miR-450b-5p induced by oncogenic KRAS is required for colorectal cancer progression. Collectively, our work helped to understand the precise role of miR-450b-5p in the progression of CRC, and might promote the development of new therapeutic strategies against CRC.

The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas

“…Although alterations such as gene amplification, deletion, and translocation are common events in genomic regions hosting miRNAs and can influence their expression in cancer (66), direct regulation by oncogenes and tumor suppressors can also significantly influence miRNA expression levels (27)(28)(29)(30)(31). Previous studies have suggested upregulation and functional roles for miR21, miR450b-5p, and miR30c in response to oncogenic KRAS in cancer (14)(15)(16)(17). Here we used primary MEFs with conditional expression of oncogenic KRAS (36) to identify key dysregulated miRNAs.…”

“…An alternative mechanism for regulation of gene expression is via microRNAs (miRNAs) (13). However, our understanding of the role of miRNAs functionally regulating the consequences of KRAS activation is still limited (14)(15)(16)(17). The study of miRNA function is an alternative strategy to yield molecular insights necessary for the development of novel therapies against KRAS-driven tumors.…”

“…For example, pioneering studies described overexpression of MYC (26) or mutations in TP53 (27)(28)(29)(30)(31) as drivers of miRNA expression. Comparatively fewer studies have focused on miRNAs with a pro-oncogenic role in the context of mutant-KRAS tumorigenesis (14,15,32,33), in contrast with the wealth of information about tumor-suppressive miRNAs reported to downregulate KRAS expression (34,35). In addition, functional validation of miRNAs involved in KRAS-driven oncogenesis has focused primarily on the role of such miRNAs in tumor initiation (14,15), with less attention on their role in tumor progression.…”

“…Comparatively fewer studies have focused on miRNAs with a pro-oncogenic role in the context of mutant-KRAS tumorigenesis (14,15,32,33), in contrast with the wealth of information about tumor-suppressive miRNAs reported to downregulate KRAS expression (34,35). In addition, functional validation of miRNAs involved in KRAS-driven oncogenesis has focused primarily on the role of such miRNAs in tumor initiation (14,15), with less attention on their role in tumor progression. To our knowledge, no miRNAs clearly functioning in tumor maintenance in KRAS-driven cancers have definitively been identified.…”

Downregulation of Siah1 promotes colorectal cancer cell proliferation and migration by regulating AKT and YAP ubiquitylation and proteasome degradation

“…Previous studies have shown that Siah1 is a target of MiRNAs [9][10][11] and other proteins [12] that are likely to affect the occurrence and progress of tumor [13]. Recent studies [14][15][16][17][18] have found that Siah1 plays an important role in promoting apoptosis under hypoxic conditions or by the P53-induced pathway, and during the process of tumor development, Siah1 behaves as a tumor suppressor.…”