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

Abstract

AbstractSRY-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 thatSOX9could 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 thatSOX9was upregulated in 275 COAD (colon adenocarcinoma) samples relative to 349 normal tissues. Besides, we also proved the upregulation ofSOX9in CRC cell lines (HCT15, SW480, SW1116, and HT-29) compared to normal NCM-460 cells. Silencing ofSOX9suppressed cell growth, stemness, migration, and invasion. Mechanistically, SOX9 activated the transcription of lncRNA phenylalanyl-tRNA synthetase subunit alpha antisense RNA 1 (FARSA-AS1), whileFARSA-AS1elevatedSOX9in turn by absorbingmiR-18b-5pand augmentedFARSAvia sequesteringmiR-28-5p. Furthermore, loss ofFARSA-AS1hindered malignant phenotypes in vitro and blocked tumor growth and metastasis in vivo. Notably, we testified thatFARSA-AS1aggravated the malignancy in CRC by enhancingSOX9andFARSA. Our study unveiled a mechanism of SOX9-FARSA-AS1-SOX9/FARSAloop in CRC, which provides some clews of promising targets for CRC.