Steroid receptor RNA activator gene footprint in the progression and drug resistance of colorectal cancer through oxidative phosphorylation pathway

Background: The steroid receptor RNA activator 1 (SRA1) gene is involved in the progression of various cancers via different molecular mechanisms mediated by long non-coding RNA SRA (lncRNA SRA). This study aimed to evaluate the lncRNA SRA effect on the tumor progression of colorectal cancer (CRC).

Methods: SRA1 expression was assessed in the cancer genome atlas datasets, CRC cell lines, and tumor specimens. Meta-analysis and gene co-expression network analysis were performed to identify pathways related to SRA1. RNA interference and cell treatment were utilized to examine the role of SRA1 expression in HT-29 and Caco-2 cell lines. Also, the effect of SRA1 expression was investigated on drug resistance, clinical parameters, and mutations in CRC samples.

Results: The SRA1 transcripts, especially lncRNA SRA, were dysregulated in CRC tissue samples compared with normal tissue samples. Furthermore, SRA1 depletion decreased colony formation and proliferation while induced apoptosis in HT-29 and Caco-2 cells. In silico analyses indicated that SRA1 level was correlated with expression levels of oxidative phosphorylation (OXPHOS) genes. LncRNA SRA expression increased in response to the increased oxidative capacity, and when lncRNA SRA was knocked down, the expression level of OXPHOS pathway genes, including NDUFB5 and ATP5F1B, was changed. Also, KRAS-mutant samples had the highest SRA1 expression level.

Conclusions: LncRNA SRA could function as an oncogene through the OXPHOS pathway in CRC, and serve as a potential biomarker for identifying CRC subtype with KRAS mutations. The findings suggest that lncRNA SRA might be a therapeutic target to inhibit cell proliferation in CRC.