P28^GANK Presents Degradation Of Oct4Sm Promotes Expansion Of Tumor-Initiating Gells In Hepatocarcinogenesis

The significance of tumor-initiating cells, T-ICs (also called cancer stem cells,CSCs) in tumorigenesis was initially demonstrated in leukemia and was recentlyreported for a variety of solid tumors, including breast, brain, prostate, and coloncancers. Accumulating experimental data suggest that tumor-initiating cells containthe complete genetic programs necessary to initiate and sustain tumor growth becauseof their strong self-renewal capacity. Additionally, tumor-initiating cells exhibit higherchemo-or radiation-resistance than non-tumor-initiating cells in the tumor, and areconsidered more metastatic and are likely responsible for tumor relapse. Therefore,targeted therapies aimed at eradicating tumor-initiating cells could lead todevelopment of more effective cancer treatment strategies.Hepatocellular carcinoma (HCC) is the third leading cause of cancer-relateddeath worldwide with heterogeneity and an origin that has yet to be elucidated.Several lines of evidence indicate that human liver tumor-initiating cells are criticalfor hepatocarcinogenesis. Recent studies indicate that a variety of stem cell markers,including CD133, CD90, epithelial cell adhesion molecule (EpCAM),CD24andCD13could be used for T-IC characterization. We recently identified OV6as a novelhepatic progenitor biomarker, since the subset of OV6+HCC cells possess a greaterability to form tumor in vivo and show a substantial resistance to standardchemotherapy. However, pathways that regulate expansion and function oftumor-initiating cells remain unclear.p28^GANK(also known as Gankyrin, PSMD10or p28) was identified as anoncoprotein frequently overexpressed in human liver cancers, which increases thehyperphosphorylation of Rb by CDK4and promotes the ubiquitylation of p53byMDM2, subsequently promotes their degradation by26S proteasome. Overexpressionof p28^GANKalso prevents the nuclear localization of NF-κB to inhibit its transcriptional activity. Moreover, downregulation of p28^GANKby RNA interferencecan induce apoptosis through the death receptor pathway and the mitochondrialpathway. Thus, p28^GANKplays an important role in cell proliferation, apoptosis, cellcycle and DNA damage repair. We previously demonstrated that p28^GANKpromotedHCC progression and metastasis. However, the role of p28^GANKin expansion of HCCstem cells during liver carcinogenesis and progression remains to be determined.In the present study, we investigated the role of p28^GANKin regulating function ofliver T tumor-initiating cells. We showed that p28^GANKis preferentially expressed inliver tumor-initiating cells and acts to expand the stem cell population by enhancingthe self-renewal capacity, tumorigenecity, metastasis potential, and chemoresistance,as well as inhibiting cell differentiation. Mechanistically, p28^GANKmay upregulate theexpression of transcription factor Oct4, a critical player in maintaining theself-renewal state of stem cells through impeding ubiquitination and degradation ofOct4by WWP2. These data identify oncoprotein p28^GANKas a novel effector in livertumor-initiating cells during HCC progression. Inhibitors of p28^GANKmight thereforebe developed to inactivate T-ICs and slow tumor progression.