MiR-23a-3p is a Key Regulator of IL-17C-Induced Tumor Angiogenesis in Colorectal Cancer.

Yunna Lee,Jieun Choo,Jin-Wook Yoo,Yunjin Jung,Eunok Im,Sang Hoon Rhee,Su Jin Kim,Gwangbeom Heo

doi:10.3390/cells9061363

Yunna Lee, Jieun Choo + Show 6 more

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https://doi.org/10.3390/cells9061363

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Journal: Cells	Publication Date: Jun 1, 2020
Citations: 27	License type: CC BY 4.0

Affiliation: Pusan National University, Oakland University

Abstract

MicroRNAs (miRNAs) have emerged as key players in tumor angiogenesis. Interleukin-17C (IL-17C) was identified to promote colorectal cancer (CRC) progression. Therefore, we aimed to investigate the effect of IL-17C on tumor angiogenesis, the involvement of miR-23a-3p in IL-17C signaling, and the direct target gene of miR-23a-3p in CRC. In vitro and ex vivo angiogenesis, a mouse xenograft experiment, and immunostaining were performed to test the effect of IL-17C on tumor angiogenesis. ELISA, quantitative real time PCR, and gene silencing were used to uncover the underlying mechanism. IL-17C induced angiogenesis of intestinal endothelial cells, subsequently enhancing cell invasion and migration of DLD-1 cells. IL-17C-stimulated DLD-1 cells produced vascular endothelial growth factor (VEGF) to enhance angiogenesis. Moreover, IL-17C markedly accelerated xenograft tumor growth, which was manifested by substantially reduced tumor growth when treated with the VEGF receptor 2 inhibitor Ki8751. Accordingly, Ki8751 suppressed the expression of IL-17C-stimulated PECAM and VE-cadherin in xenografts. Furthermore, IL-17C activated STAT3 to increase the expression of miR-23a-3p that suppressed semaphorin 6D (SEMA6D) expression, thereby permitting VEGF production. Taken together, our study demonstrates that IL-17C promotes tumor angiogenesis through VEGF production via a STAT3/miR-23a-3p/SEMA6D axis, suggesting its potential as a novel target for anti-CRC therapy.

Highlights

Colorectal cancer (CRC) is the third most common cancer type and the major leading cause of cancer death worldwide [1]
Our results showed that IL-17C (100 ng/mL, 4 h) enhanced tube formation of Human intestinal microvascular endothelial cells (HIMECs) cultured on Matrigel (Figure 1B)
These results indicate that IL-17C exerts a potent angiogenic activity in vitro and ex vivo, by promoting cell migration

Summary

Introduction

Colorectal cancer (CRC) is the third most common cancer type and the major leading cause of cancer death worldwide [1]. Incidence rates are increasing with economic development and westernization of lifestyle in Asian and African countries [2]. The Republic of Korea has the highest age-standardized CRC incidence rate globally [3]. The molecular mechanism underlying tumor angiogenesis is still limited. The IL-17 family consists of six cytokines including IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F [5]. Recent clinical and non-clinical studies suggest an association between the IL-17 family and the progression of various tumor types such as gastric, hepatocellular, breast, and colorectal cancer (CRC) [8,9,10,11,12].

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