Identification of RNA-splicing factor Lsm12 as a novel tumor-associated gene and a potent biomarker in Oral Squamous Cell Carcinoma (OSCC)

Abstract

Background Oral squamous cell carcinoma (OSCC) is one of the common cancers worldwide. The lack of specific biomarkers and therapeutic targets leads to delayed diagnosis and hence the poor prognosis of OSCC patients. Thus, it is urgent to identify effective biomarkers and therapeutic targets for OSCC. Methods We established the golden hamster carcinogenic model of OSCC induced by 7,12-dimethylbenz(a) anthrancene (DMBA) and used mRNA microarrays to detect the differentially expressed genes (DEGs). DEGs were validated in OSCC clinical tissue microarrays using immunohistochemistry method. Whole transcriptome sequencing was performed to obtain an overview of biological functions of Lsm12. PCR assay and sequencing were employed to investigate the alternative splicing of genes regulated by Lsm12. Cell proliferation, colony formation, Transwell migration and invasion assay and in vivo tumor formation assay were performed to investigate the roles of Lsm12 and two transcript variants of USO1 in OSCC cells. Results Lsm12 was identified to be significantly up-regulated in the animal model of OSCC tumorigenesis, which was validated in the clinical OSCC samples. In the paired normal tissues, Lsm12 staining was negative (91%, 92/101) or weak, while in OSCC tissues, positive rate is 100% and strong staining spread over the whole tissues in 93 (93/101, 92%) cases. Lsm12 overexpression significantly promoted OSCC cell growth, colony formation, migration and invasion abilities, while Lsm12 knockdown showed the opposite trends on these phenotypes and obviously inhibited the tumor formation in vivo. Furthermore, Lsm12 overexpression caused the inclusion of USO1 exon 15 and Lsm12 knockdown induced exon 15 skipping. Exon 15-retained USO1 significantly promoted the malignant phenotypes of OSCC cells when compared with the exon 15-deleted USO1. Conclusions We identified Lsm12, a novel tumorigenesis-related gene, as an important regulator involved in OSCC tumorigenesis. Lsm12 is a novel RNA-splicing related gene and can regulate the alternative splicing of USO1 exon 15 which was associated closely with OSCC carcinogenesis. Our findings thus provide that Lsm12 might be a potent biomarker and potential therapeutic target for OSCC.

LSM12 facilitates the progression of colorectal cancer by activating the WNT/CTNNB1 signaling pathway

“…It is one of the main factors participating in DNA damage induced by oxidative stress [15]. Heretofore, the research on the function of LSM12 in human malignant tumors is still very limited [16][17][18]. Here, we demonstrated that LSM12 is involved in cytopathologic and tumorigenic functions during CRC development through the regulation of CTNNB1 protein stability and CTTNB1-LEF1-TCF1 transcriptional complex formation.…”

LINC00173 blocks GATA6‐mediated transcription of COL5A1 to affect malignant development of oral squamous cell carcinoma

“…The limitations in specific biomarkers and therapeutic targets for OSCC result in delayed diagnosis and poor prognosis in patients, which makes identification of novel biomarkers and treatment targets as urgent tasks for OSCC control. 15 In this work, we identified COL5A1 as a tumor driver in OSCC activated by GATA6. LINC00173, which could bind to GATA6 to block the transcriptional activation of COL5A1, was found to suppress the malignant phenotype of cancer cells.…”

Emerging roles of alternative RNA splicing in oral squamous cell carcinoma

“…LSM12 is significantly upregulated in OSCC tissues of patients and animal models. LSM12 is required for OSCC cell proliferation, migration, and tumorigenesis (45).…”

“…Full-length USO1 isoform was positively associated with OSCC cell proliferation and enhanced tumorigenic capacity, while USO1 short isoform without exon 15 showed the opposite effects on OSCC cell proliferation and cell cycle progression. LSM12 promotes USO1 exon 15 inclusion (45). Alternative RNA splicing and splicing factors regulate OSCC cell proliferation, invasion, and EMT.…”