hnRNPK promotes gastric tumorigenesis through regulating CD44E alternative splicing

Abstract

Background: The 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.Methods: Here 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.Results: The 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). Conclusion:These findings revealed the importance of the hnRNPK-SRSF1-CD44E axis in promoting gastric tumorigenesis.

Inhibition of circRNA circVPS33B reduces cell malignant behaviors and Warburg effect through regulation of the miR-873-5p/HNRNPK axis in infiltrative gastric cancer

“…Xu et al proved that HNRNPK promoted cell colony formation and proliferation in lung adenocarcinoma cells [36]. Peng et al reported that HNRNPK contributed to cell invasion, migration, and proliferation via regulation of the alternative splicing of CD44E in GC cells [26]. In our work, we discovered that HNRNPK was a target of miR-873-5p.…”

Inhibition of circRNA circVPS33B reduces cell malignant behaviors and Warburg effect through regulation of the miR-873-5p/HNRNPK axis in infiltrative gastric cancer 

“…Xu et al proved that HNRNPK promoted cell colony formation and proliferation in lung adenocarcinoma cells through elevating YAP expression [36]. Peng et al reported that HNRNPK contributed to the invasion, migration, and proliferation of GC cells via regulation of the alternative splicing of CD44E [26]. In our work, we discovered that HNRNPK was a target of miR-873-5p.…”

“…Moreover, high HNRNPK level is related to poor prognosis and development in several cancers, such as bladder cancer [24] and colorectal cancer [25]. HNRNPK was also revealed to facilitate the progression of GC [26]. Nevertheless, the mechanisms associated with HNRNPK in in ltrative GC development are relatively less known.…”

Hypoxia-Induced Adaptations of miRNomes and Proteomes in Melanoma Cells and Their Secreted Extracellular Vesicles

“…We found three proteins (HNRNPL, HNRNPK, RAN) upregulated in hEVs, which were associated with decreased survival. Hypoxia has been shown to induce the transport of HNRNPL from the nucleus to the cytoplasm where it can stabilise VEGFA [53] and HNRNPK has been reported to be involved in the tumorigenesis of lung and gastric cancer cells [54,55] while RAN was found to play an important role in the nuclear-cytoplasmic transport of proteins under hypoxia [56].…”