Genetic dissection of the miR-200–Zeb1 axis reveals its importance in tumor differentiation and invasion

Abstract

The epithelial-to-mesenchymal transition (EMT) is an important mechanism for cancer progression and metastasis. Numerous in vitro and tumor-profiling studies point to the miR-200–Zeb1 axis as crucial in regulating this process, yet in vivo studies involving its regulation within a physiological context are lacking. Here, we show that miR-200 ablation in the Rip-Tag2 insulinoma mouse model induces beta-cell dedifferentiation, initiates an EMT expression program, and promotes tumor invasion. Strikingly, disrupting the miR-200 sites of the endogenous Zeb1 locus causes a similar phenotype. Reexpressing members of the miR-200 superfamily in vitro reveals that the miR-200c family and not the co-expressed and closely related miR-141 family is responsible for regulation of Zeb1 and EMT. Our results thus show that disrupting the in vivo regulation of Zeb1 by miR-200c is sufficient to drive EMT, thus highlighting the importance of this axis in tumor progression and invasion and its potential as a therapeutic target.

C/EBPδ demonstrates a dichotomous role in tumor initiation and promotion of epithelial carcinoma

“…This study highlights new roles for C/EBPδ in HGSC and separately features intriguing EMT/MET hybrid FTE phenotypes influenced by the ovulatory cycle. This hybrid-pleiotropic phenotype in cancer is implicated in cancer metastasis, cancer stem cell plasticity, chemoresistance and immune evasion (Mittal 2018, Title, Hong et al 2018, all features also attributed to ovarian cancer biology and heterogeneity. These EMT/MET hybrid protein expressions observed in the histologically normal fallopian tube epithelia and pre-malignant lesions need further study to identify core transcriptional and genomic/epigenomic networks driving fallopian tube epithelia transformation.…”

Systematic characterization of non‐coding RNAs in triple‐negative breast cancer

“…Emerging evidence suggests that miRNAs are associated with the metastatic process in TNBC. Dysregulated expression of miR‐200 family members has been observed in multiple cancers 42,43 . However, the roles of miR‐200 family members in the metastasis of breast cancer are still disputable.…”

Immunomodulatory MicroRNAs in cancer: targeting immune checkpoints and the tumor microenvironment

“…It is noteworthy that MYC protooncogene induces hypermethylation of miR-200b promoter leading to its repression in triple-negative BCC [101]. The depletion of miR-200 halts pancreatic b-cell differentiation and initiates EMT leading to augmented tumor invasion in vivo, in an insulinoma mouse model through Zeb1 regulation [102]. The overexpression of miR-6883 in CRC cells resulted in reduced levels of CDK4 and 6 with subsequent cell cycle arrest at G0/G1 phase [103].…”