SOX9-activated FARSA-AS1 predetermines cell growth, stemness, and metastasis in colorectal cancer through upregulating FARSA and SOX9

Taicheng Zhou,Zhen Zong,Ning Ma,Yingru Li,Zhuomin Yu,Fuxin Tang,Lili Wu,Zhipeng Jiang,Kunpeng Hu

doi:10.1038/s41419-020-03273-4

Abstract

SRY-box transcription factors (SOXs) are effective inducers for the formation of stem-like phenotypes. As a member of SOX family, SOX9 (SRY-box transcription factor 9) has been reported to be highly expressed and exert oncogenic functions in multiple human cancers. In this study, we hypothesized that SOX9 could regulate the function of cancer stem/initiating cells (CSCs) to further facilitate the progression of colorectal cancer (CRC). Then, stable transfection of shRNAs was used to silence indicated genes. Loss-of-function experiments were conducted to demonstrate the in vitro function of CRC cells. In vivo study was conducted to determine the changes in tumorigenesis and metastasis in vivo. Bioinformatics analyses and mechanistic experiments were employed to explore the downstream molecules. Presently, GEPIA data indicated that SOX9 was upregulated in 275 COAD (colon adenocarcinoma) samples relative to 349 normal tissues. Besides, we also proved the upregulation of SOX9 in CRC cell lines (HCT15, SW480, SW1116, and HT-29) compared to normal NCM-460 cells. Silencing of SOX9 suppressed cell growth, stemness, migration, and invasion. Mechanistically, SOX9 activated the transcription of lncRNA phenylalanyl-tRNA synthetase subunit alpha antisense RNA 1 (FARSA-AS1), while FARSA-AS1 elevated SOX9 in turn by absorbing miR-18b-5p and augmented FARSA via sequestering miR-28-5p. Furthermore, loss of FARSA-AS1 hindered malignant phenotypes in vitro and blocked tumor growth and metastasis in vivo. Notably, we testified that FARSA-AS1 aggravated the malignancy in CRC by enhancing SOX9 and FARSA. Our study unveiled a mechanism of SOX9-FARSA-AS1-SOX9/FARSA loop in CRC, which provides some clews of promising targets for CRC.

Highlights

Colorectal cancer (CRC) has been reported as one of the most malignant cancers in the world[1,2]
SRY-box transcription factor 9 (SOX9) is upregulated in CRC cells and promotes cell growth, stemness, migration, and invasion According to the data from GEPIA, we found that SOX9 was upregulated in colon adenocarcinoma (COAD) tissues (Fig. 1A)
We identified that no SOX9 mutation was found in SW1116 and HT-29 cells but four kinds of SOX9 mutations were predicted in HCT15 cells by using COSMIC tool

Summary

Introduction

Colorectal cancer (CRC) has been reported as one of the most malignant cancers in the world[1,2]. It has been reported that SOX9 is involved in the progression of prostate cancer and gastric cancer by regulating WNT signaling pathway[6,7]. Zhou et al Cell Death and Disease (2020)11:1071 stemness in hepatocellular carcinoma[8,9]. Inhibited SOX9 hampers cell growth, migration, invasion, and EMT in thyroid cancer[10]. SOX9 can regulate the self-renewal of cancer stem cells in hepatocellular carcinoma[11]. The function of SOX9 in CRC still remains largely unknown. We are going to search the role and probable molecular mechanism of SOX9 in CRC

Objectives

Methods

Results

Conclusion