Abstract
BackgroundThe high prevalence of alternative splicing among genes implies the importance of genomic complexity in regulating normal physiological processes and diseases such as gastric cancer (GC). The standard form of stem cell marker CD44 (CD44S) and its alternatives with additional exons are reported to play important roles in multiple types of tumors, but the regulation mechanism of CD44 alternative splicing is not fully understood.MethodsHere the expression of hnRNPK was analyzed among the Cancer Genome Atlas (TCGA) cohort of GC. The function of hnRNPK in GC cells was analyzed and its downstream targeted gene was identified by chromatin immunoprecipitation and dual luciferase report assay. Finally, effect of hnRNPK and its downstream splicing regulator on CD44 alternative splicing was investigated.ResultsThe expression of hnRNPK was significantly increased in GC and its upregulation was associated with tumor stage and metastasis. Loss-of-function studies found that hnRNPK could promote GC cell proliferation, migration, and invasion. The upregulation of hnRNPK activates the expression of the splicing regulator SRSF1 by binding to the first motif upstream the start codon (− 65 to − 77 site), thereby increasing splicing activity and expression of an oncogenic CD44 isoform, CD44E (has additional variant exons 8 to 10, CD44v8-v10).ConclusionThese findings revealed the importance of the hnRNPK-SRSF1-CD44E axis in promoting gastric tumorigenesis.
Highlights
The high prevalence of alternative splicing among genes implies the importance of genomic complex‐ ity in regulating normal physiological processes and diseases such as gastric cancer (GC)
We demonstrated that the expression of Heterogeneous nuclear ribonucleoprotein K (hnRNPK) was significantly increased in GC and its upregulation was associated with tumor stage and metastasis
The expression of hnRNPK is upregulated in GC patients We first analyzed the expression pattern of hnRNPK mRNA in a total of 374 clinical samples of GC and 47 normal controls in the Cancer Genome Atlas (TCGA) datasets
Summary
The high prevalence of alternative splicing among genes implies the importance of genomic complex‐ ity in regulating normal physiological processes and diseases such as gastric cancer (GC). The standard form of stem cell marker CD44 (CD44S) and its alternatives with additional exons are reported to play important roles in multiple types of tumors, but the regulation mechanism of CD44 alternative splicing is not fully understood. Alternative splicing of pre-mRNA transcripts is an important process by which genomic complexity is generated from the relatively lower number of genes. About 90% of human genes could produce alternatively spliced forms [7, 8]. The pre-mRNA splicing process is regulated by different splicing regulators, and their deregulations often result in aberrantly spliced individual variants and aberrant gene expression profiles. Intensive studies on splice variants have revealed that aberrant splicing contributes to a number of human
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