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Abstract
Hepatic metastasis is responsible for the majority of colorectal cancer (CRC)-related mortalities. Although Gankyrin (PSMD10) has been implicated in cancer metastasis, its exact role and underlying mechanisms of CRC hepatic metastasis remain largely unknown. Herein, we showed that the expression of Gankyrin was higher in primary CRC with hepatic metastasis compared with CRC without metastasis. RNAi-mediated silencing of Gankyrin expression in highly metastatic human CRC cells impaired their migratory and metastatic capacity in vivo. Genome-wide transcriptome profiling revealed activation of the interleukin (IL)-8 signaling pathway by Gankyrin. Protein levels of IL-8 and cyclin D1 (CCND1), the two important molecules in the IL-8 pathway, were positively correlated with Gankyrin expression in human CRC specimens. Furthermore, genetic deletion of cyclin D1 showed its requirement in Gankyrin-mediated cell migration. Finally, administration of recombinant IL-8 rescued the migratory defect of CRC cells where Gankyrin expression was silenced. Together, our findings highlight the importance of Gankyrin in hepatic metastasis of CRC and point out its candidature as a potential prognostic marker and therapeutic target to improve the clinical management of metastatic CRC.
Highlights
Gankyrin was initially identified as the p28 component, a regulatory subunit of the 26S proteasome complex [1]
Elevated Gankyrin expression in primary colorectal cancers with hepatic metastasis We previously reported that Gankyrin is overexpressed in human lung and breast cancers and plays an essential role in breast cancer metastasis [10, 16]
The role of Gankyrin in tumorigenesis has been well established in a variety of human malignancies including hepatocellular carcinoma (HCC), esophageal equamous cell carcinoma, breast, pancreatic, oral, lung, and colorectal cancer (CRC) [4, 6,7,8, 10, 16, 19, 39, 40]
Summary
Gankyrin ( known as PSMD10 or p28gank or nas6) was initially identified as the p28 component, a regulatory subunit of the 26S proteasome complex [1]. Gankyrin consists of 7 ankyrin repeats, which are required for protein–protein interactions [2,3,4]. The expression of Gankyrin has been investigated in a variety of cancers with nearly universal findings that showed elevated protein and/or mRNA levels in cancers when compared with normal counterparts [4,5]. Gankyrin has been shown to be involved in carcinogenesis and oncogene-induced tumor onset and progression [4, 6,7,8,9,10]. Overexpression of Gankyrin promotes cellular proliferation by targeting retinoblastoma protein (Rb), leading to subsequent Rb degradation, activation of E2F transcription factor, and DNA synthesis of genes required for G1–S-phase transition [11,12,13].
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