Inclusion of hnRNP L Alternative Exon 7 Is Associated with Good Prognosis and Inhibited by Oncogene SRSF3 in Head and Neck Squamous Cell Carcinoma

Abstract EN

Background and Objectives.

Alternative splicing is increasingly associated with cancers.

HnRNP L is a splicing factor that promotes carcinogenesis in head and neck squamous cell carcinoma (HNSCC) and other cancers.

Alternative exon 7 of hnRNP L contains an in-frame stop codon.

Exon 7-included transcripts can be degraded via nonsense-mediated decay or encode a truncated hnRNP L protein.

Exon 7-excluded transcripts can encode full-length functional hnRNP L protein.

HnRNP L has an autoregulation mechanism by promoting the inclusion of its own exon 7.

This study aimed to understand the relationship between the alternative splicing of exon 7 and HNSCC.

Oncogenic splicing factor SRSF3 has an alternative exon 4 and similar autoregulation mechanism.

HnRNP L promotes SRSF3 exon 4 inclusion and then inhibits SRSF3 autoregulation.

Materials and Methods.

The relationship between alternative splicing of hnRNP L exon 7 and clinical characteristics of HNSCC in a TCGA dataset was analyzed and confirmed by RT-PCR in a cohort of 61 oral squamous cell carcinoma (OSCC) patients.

The regulators of exon 7 splicing were screened in 29 splicing factors and confirmed by overexpression or silencing assay in HEK 293, CAL 27, and SCC-9 cell lines.

Results.

The inclusion of hnRNP L exon 7 was significantly negatively associated with the progression and prognosis of HNSCC, which was confirmed in the cohort of 61 OSCC patients.

SRSF3 inhibited exon 7 inclusion and hnRNP L autoregulation and then promoted the expression of full-length functional hnRNP L protein.

SRSF3 exon 4 inclusion was correlated with hnRNP L exon 7 inclusion in both HNSCC and breast cancer.

HNSCC patients with both low hnRNP L exon 7 and SRSF3 exon 4 inclusion show poor overall survival.

Conclusions.

Inclusion of hnRNP L alternative exon 7 is associated with good prognosis and inhibited by oncogene SRSF3 in HNSCC.