Cytoplasmic Accumulation of Heterogeneous Nuclear Ribonucleoprotein K Strongly Promotes Tumor Invasion in Renal Cell Carcinoma Cells

Abstract

Heterogeneous nuclear ribonucleoprotein (hnRNP) K is a part of the ribonucleoprotein complex which regulates diverse biological events. While overexpression of hnRNP K has been shown to be related to tumorigenesis in several cancers, both the expression patterns and biological mechanisms of hnRNP K in renal cell carcinoma (RCC) cells remain unclear. In this study, we showed that hnRNP K protein was strongly expressed in selected RCC cell lines (ACHN, A498, Caki-1, 786–0), and knock-down of hnRNP K expression by siRNA induced cell growth inhibition and apoptosis. Based on immunohistochemical (IHC) analysis of hnRNP K expression in human clear cell RCC specimens, we demonstrated that there was a significant positive correlation between hnRNP K staining score and tumor aggressiveness (e.g., Fuhrman grade, metastasis). Particularly, the rate of cytoplasmic localization of hnRNP K in primary RCC with distant metastasis was significantly higher than that in RCC without metastasis. Additionally, our results indicated that the cytoplasmic distribution of hnRNP K induced by TGF-β stimulus mainly contributed to TGF-β-triggered tumor cell invasion in RCC cells. Dominant cytoplasmic expression of ectopic hnRNP K markedly suppressed the inhibition of invasion by knock-down of endogenous hnRNP K. The expression level of matrix metalloproteinase protein-2 was decreased by endogenous hnRNP K knock-down, and restored by ectopic hnRNP K. Therefore, hnRNP K may be a key molecule involved in cell motility in RCC cells, and molecular mechanism associated with the subcellular localization of hnRNP K may be a novel target in the treatment of metastatic RCC.

Heterogeneous nuclear ribonucleoprotein K is associated with poor prognosis and regulates proliferation and apoptosis in bladder cancer

“…Here, we discovered that hnRNPK knockdown significantly inhibited bladder cancer cell proliferation in vitro and tumour growth in vivo by inducing G0/G1 arrest. Supporting our findings, recent studies have found that hnRNPK down-regulation suppressed cell proliferation in pancreatic cancer [15] and renal cell carcinoma [18] in vitro, but the underlying mechanism remains largely unknown. Through RNA-seq analysis and ChIP, we determined that hnRNPK regulates cyclin D1 and G0S2 transcription.…”

“…Balasubramani et al showed that hnRNPF was a potential marker for colorectal cancer progression [29]. Aberrant hnRNPK expression in the cytoplasm has been reported in pancreatic cancer [15], colorectal cancer [16], prostate cancer [17], and renal cell carcinoma [18], and was associated with poor clinical prognosis. However, the expression and biological functions of hnRNPK underlying tumorigenesis and progression in bladder cancer remain unknown.…”

“…hnRNPK is overexpressed in human cancers, including colorectal, pancreatic, liver, prostate and renal cancer [14][15][16][17][18]. Heterogeneous nuclear ribonucleoprotein K is thought to play an important role in cancer progression, as high levels of expression correlate with poor clinical outcome [16][17][18]. Several studies have found that hnRNPK promoted metastases in tumours by up-regulating matrix metalloproteinase [18][19][20].…”

Estrogen receptor α (ERα) indirectly induces transcription of human renal organic anion transporter 1 (OAT1)

“…chromatin remodeling, transcription, splicing, translation, and mRNA stability. The 464 aa HNRNPK protein harbors three consecutive K homology (KH) domains responsible for RNA and DNA binding, a nuclear localization signal and a nuclear shuttling domain, allowing HNRNPK to move across the cell compartments (Otoshi et al, ). For our study, the ability to act as transcription factor was of great interest (Michelotti et al, ).…”

Identificação de proteínas reguladoras do <i>splicing</i> associadas à microRNAs.

“…Foi identificado um papel de supressor de apoptose em carcinoma hepatocelular (HCC) da proteína hnRNP_K, independente do status de regulação da p53 e caspases (Xiao et al, 2013). Já em câncer renal, foi observado um acúmulo citoplasmático de hnRNP_K, o que promove uma maior invasão do tumor por meio do estímulo de TGF-β (Otoshi et al, 2015).…”