Increased expression of the heterogeneous nuclear ribonucleoprotein K in pancreatic cancer and its association with the mutant p53

Abstract

The heterogeneous nuclear ribonucleoprotein (hnRNP) K is an essential RNA and DNA binding protein involved in gene expression and signal transduction including DNA transcription, RNA splicing, RNA stability and translation. The role of hnRNP K in cancer is relatively understudied. However, several cellular functions strongly indicate that hnRNP K is involved in tumorigenesis. In this study, we investigated the altered protein expression and the subcellular distribution of the hnRNP K protein using tissue microarrays in pancreatic cancer. We showed an increased cytoplasmic hnRNP K in pancreatic cancer. This increase in hnRNP K protein occurs at the posttranscriptional level. We postulate that the cytoplasmic accumulation of hnRNP K will lead to silenced mRNA translation of tumor suppressor genes and thus contributes to pancreatic cancer development. We also demonstrated that knocking down of hnRNP K expression by siRNA inhibited pancreatic cancer cell growth and colony formation. hnRNP K was identified as a member of the p53/HDM2 pathway. Whether hnRNP K interacts with the mutant p53 is not known. Using two different pancreatic cancer cell lines, we can demonstrate that hnRNP K interacts with the mutant p53. The subcellular distribution and function of the mutant p53 and the interaction of hnRNP K/ mutant p53 were affected by the Ras/MEK/ERK pathway, growth factors and the specific p53 mutations in pancreatic cancer cells. Since Kras is activated and p53 is mutated in most pancreatic cancers, these data unveiled an important new signaling pathway that linked by hnRNP K and mutant p53 in pancreatic cancer tumorigenesis.The heterogeneous nuclear ribonucleoprotein (hnRNP) K, a component of the hnRNP complex, is an essential RNA and DNA binding protein. Genetic studies in C. elegans and metazoans reveal that hnRNP K deletion is embryonic lethal.

Splicing-factor alterations in cancers

“…Together, these data suggest that hnRNPK can act as a tumor suppressor in hematological disorders. Conversely, hnRNPK was shown to be overexpressed in a variety of cancers, including breast, esophageal squamous cell, pancreatic, skin, colorectal, and oral squamous cell carcinoma (Mandal et al 2001;Carpenter et al 2006;Roychoudhury and Chaudhuri 2007;Zhou et al 2010). hnRNPK overexpression results in enhanced malignancy and metastasis in vitro, at least in part through alternative splicing of target genes that regulate the extracellular matrix, cell motility, and angiogenesis (Gao et al 2013).…”

The expression profile of RNA-binding proteins in primary and metastatic colorectal cancer: relationship of heterogeneous nuclear ribonucleoproteins with prognosis☆

“…hnRNPK is the most widely studied, and its expression and the significance of its expression have been investigated in several types of cancer including colorectal cancer, prostate cancer, pancreatic cancer, oral cancer, nasopharyngeal cancer, and cervical cancer [13][14][15][16][17][18][19][20][21][22][23].…”

Proteomics-based analysis of differentially expressed proteins in the CXCR1-knockdown gastric carcinoma MKN45 cell line and its parental cell

“…Interestingly, 4IF4E transcription is up-regulated when both c-myc and hnRNPK are co-overexpressed [46], suggesting that hnRNPK may cooperate with additional oncoproteins which are permissive toward cancerous growth. In breast cancer cells [47], prostate carcinoma [48], and pancreatic cancer [49], plenty of researches demonstrated that hnRNPK significantly enhances the proliferative activity of tumor cells. Besides that, several research findings have confirmed that there is a close relation between hnRNPK and tumorigenesis.…”