MicroRNA-130b Promotes Tumor Development and Is Associated with Poor Prognosis in Colorectal Cancer

Abstract

MicroRNA-130b (miR-130b) is involved in several biologic processes; its role in colorectal tumorigenesis has not been addressed so far. Herein, we demonstrate that miR-130b up-regulation exhibits clinical relevance as it is linked to advanced colorectal cancers (CRCs), poor patients' prognosis, and molecular features of enhanced epithelial-mesenchymal transition (EMT) and angiogenesis. miR-130b high-expressing cells develop large, dedifferentiated, and vascularized tumors in mouse xenografts, features that are reverted by intratumor injection of a specific antisense RNA. In contrast, injection of the corresponding mimic in mouse xenografts from miR-130b low-expressing cells increases tumor growth and angiogenic potential while reduces the epithelial hallmarks. These biologic effects are reproduced in human CRC cell lines. We identify peroxisome proliferator-activated receptor γ (PPARγ) as an miR-130b direct target in CRC in vitro and in vivo. Notably, the effects of PPARγ gain- and loss-of-function phenocopy those due to miR-130b down-regulation or up-regulation, respectively, underscoring their biologic relevance. Furthermore, we provide mechanistic evidences that most of the miR-130b-dependent effects are due to PPARγ suppression that in turn deregulates PTEN, E-cadherin, Snail, and vascular endothelial growth factor, key mediators of cell proliferation, EMT, and angiogenesis. Since higher levels of miR-130b are found in advanced tumor stages (III-IV), we propose a novel role of the miR-130b-PPARγ axis in fostering the progression toward more invasive CRCs. Detection of onco-miR-130b and its association with PPARγ may be useful as a prognostic biomarker. Its targeting in vivo should be evaluated as a novel effective therapeutic tool against CRC.

miR-130b regulates the proliferation, invasion and apoptosis of glioma cells via targeting of CYLD

“…Recently, miR-130b was demonstrated to have tumor suppressive and cancer-promoting properties depending on the tumor type. miR-130b is highly expressed in melanoma (9), gastric (10), bladder (11) and colorectal cancer (12), esophageal squamous cell carcinoma (13) and glioma (14), but significantly and poorly expressed in papillary thyroid carcinomas (15), endometrial cancer (16), pituitary adenomas (17) and pancreatic cancer (18). Previously, miR-130b was observed to be overexpressed in glioma tissues, while the suppression of the expression of miR-130b via peroxisome proliferator-activated receptor-γ (PPAR-γ) inhibited the proliferation and invasive activity of glioma (14).…”

miR-517a is an independent prognostic marker and contributes to cell migration and invasion in human colorectal cancer

“…Numerous oncomiRs are overexpressed in CRC compared with noncancerous tissues, including miR-494, miR-21, miR-23a and miR-130b (8)(9)(10)(11). These oncomiRs effect CRC cell proliferation, apoptosis, migration and invasion (12).…”

miR-130b-3p Upregulation Contributes to the Development of Thyroid Adenomas Targeting <b><i>CCDC6</i></b> Gene

“…Indeed, miR-130b upregulation has been observed in triple-negative breast cancer, where it mediates the repression of the CCNG2 gene coding for the cyclin G2 protein, a crucial cell cycle regulator [21]. Equally, miR-130b upregulation has been reported in esophageal squamous [22] and colon [23] carcinomas regulating the PTEN-Akt pathway [22]. Interestingly, miR-130b is associated with a poor prognosis in colon [23] and ovarian [24] carcinomas.…”

“…Equally, miR-130b upregulation has been reported in esophageal squamous [22] and colon [23] carcinomas regulating the PTEN-Akt pathway [22]. Interestingly, miR-130b is associated with a poor prognosis in colon [23] and ovarian [24] carcinomas.…”