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    • It has been known that RNA

    2018-10-25

    It has been known that RNA helicases are aberrantly expressed and play a key role in various solid and hematologic malignancies. In addition to their roles in RNA procession, multiple members of the DEXD/H-proteins, including DDX1, DDX3, DHX5, DHX9 and DHX17, are also implicated in transcription regulations (Abdelhaleem, 2004b; Fuller-Pace, 2006; Ishaq et al., 2009). Our previous work shows that DHX32 is up-regulated in CRC compared to its adjacent normal tissues and contributes to the growth and metastasis of CRC (Huang et al., 2009; Lin et al., 2015). However, how DHX32 regulates gene comt inhibitor is largely unknown. Our study here revealed a mechanism by which DHX32 regulates the signaling intensity of the Wnt/β-catenin pathway and controls the expression of VEGFA. We demonstrated that the multifunctional RNA helicase DHX32 also regulates gene expression at the transcription level. Tumor angiogenesis is critical for tumor growth, maintenance, and metastasis. Many studies have demonstrated that angiogenesis inhibitors have a significant therapeutic value (Zhao et al., 2011; Faivre et al., 2007). In this regard, DHX32 can be a potential druggable target for cancer treatment. Our result that ablation of DHX32 reduces microvessel density and inhibits tumor growth suggests that inhibition of DHX32 has the potential for CRC treatments. Furthermore, our result shows that high expression of DHX32 correlates with disease aggressiveness and poor outcomes of CRC patients, including short metastatic-free and overall survival times.
    Author Contributions
    Conflict of Interest
    Acknowledgements
    Introduction Metastasis is defined as the formation of secondary tumor foci in one or more organs at a distance from the primary lesion (Nguyen and Massague, 2007). Although the precise molecular events leading to the acquisition of the metastatic phenotype remain largely unclear, the coordination and cooperation of several signal transduction pathways in metastasis has been suggested. Examples of these pathways include the mitogen-activated protein kinase (MAPK) pathway (Krueger et al., 2001), focal adhesion kinase (FAK) pathway (Sieg et al., 2000), Src pathway (Yeatman, 2004) and the Akt pathway (Irie et al., 2005). The T-LAK-cell-originated protein kinase (TOPK) is a serine-threonine kinase member of the MAPKK family. We have studied TOPK function over the last few years and have shown that TOPK is involved in many cellular processes, including tumor development, cell growth, apoptosis and inflammation (Zykova et al., 2006; Oh et al., 2007; Zhu et al., 2007; Zykova et al., 2010; Li et al., 2011). We first discovered that TOPK serves as an oncogenic MEK that exerts positive feedback on ERK2 to promote colorectal cancer formation in vitro and in vivo (Zhu et al., 2007). Interest in the function of TOPK as an oncogene and in the development of new inhibitors of TOPK has dramatically increased (Vishchuk et al., 2016; Xiao et al., 2016; Zeng et al., 2016). However, a clear mechanism explaining how TOPK regulates the process of colon cancer metastasis to the liver has not yet been elucidated. In this study, we investigated the role of TOPK in colon cancer metastasis to the liver and identified the p53-related protein kinase (PRPK) as a novel substrate of TOPK. PRPK was first cloned from an interleukin-2-activated cytotoxic T-cell subtraction library and was shown to up-regulate the transcriptional activity of p53 when transfected into COS-7 cells. Thus the protein was named “p53-related protein kinase” and the authors suggested that PRPK might play an important role in cell cycle or apoptosis (Abe et al., 2001). Later these same authors concluded that they could not rule out the possibility that PRPK did not directly phosphorylate p53 due to the fact that binding and phosphorylation p53 at Ser15 was shown in the presence of an activating COS-7 cell lysate, suggesting that the phosphorylation status of p53 is regulated not only by PRPK, but also by other kinases (Abe et al., 2006). The p53 protein also remains phosphorylated on Ser15 even after depletion of PRPK, suggesting that this is not the major role of PRPK in proliferating cells (Peterson et al., 2010). Human PRPK is a homolog to the yeast kinase piD261/Bud32 (Bud32) and PRPK can partially complement Bud32 deficiency (Facchin et al., 2003). PRPK can be activated and provides a functional link between this kinase and the Akt signaling pathway (Facchin et al., 2007). However, the biological function of PRPK remains elusive. Herein we showed that TOPK is involved in colorectal cancer metastasis to the liver through its phosphorylation of PRPK at Ser250.