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Phosphoprotein enriched in diabetes (PED/PEA15) promotes migration in hepatocellular carcinoma and confers resistance to sorafenib.

ABSTRACT: Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related death with limited treatment options and frequent resistance to sorafenib, the only drug currently approved for first-line therapy. Therefore, better understanding of HCC tumor biology and its resistance to treatment is urgently needed. Here, we analyzed the role of phosphoprotein enriched in diabetes (PED) in HCC. PED has been shown to regulate cell proliferation, apoptosis and migration in several types of cancer. However, its function in HCC has not been addressed yet. Our study revealed that both transcript and protein levels of PED were significantly high in HCC compared with non-tumoral tissue. Clinico-pathological correlation revealed that PED^high HCCs showed an enrichment of gene signatures associated with metastasis and poor prognosis. Further, we observed that PED overexpression elevated the migration potential and PED silencing the decreased migration potential in liver cancer cell lines without effecting cell proliferation. Interestingly, we found that PED expression was regulated by a hepatocyte specific nuclear factor, HNF4?. A reduction of HNF4? induced an increase in PED expression and consequently, promoted cell migration in vitro. Finally, PED reduced the antitumoral effect of sorafenib by inhibiting caspase-3/7 activity. In conclusion, our data suggest that PED has a prominent role in HCC biology. It acts particularly on promoting cell migration and confers resistance to sorafenib treatment. PED may be a novel target for HCC therapy and serve as a predictive marker for treatment response against sorafenib.

SUBMITTER: Quintavalle C

PROVIDER: S-EPMC5682677 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Phosphoprotein enriched in diabetes (PED/PEA15) promotes migration in hepatocellular carcinoma and confers resistance to sorafenib.

Quintavalle Cristina C Hindupur Sravanth Kumar SK Quagliata Luca L Pallante Pierlorenzo P Nigro Cecilia C Condorelli Gerolama G Andersen Jesper Bøje JB Tagscherer Katrin Elisabeth KE Roth Wilfried W Beguinot Francesco F Heim Markus Hermann MH Ng Charlotte Kiu Yan CKY Piscuoglio Salvatore S Matter Matthias Sebastian MS

Cell death & disease 20171026 10

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related death with limited treatment options and frequent resistance to sorafenib, the only drug currently approved for first-line therapy. Therefore, better understanding of HCC tumor biology and its resistance to treatment is urgently needed. Here, we analyzed the role of phosphoprotein enriched in diabetes (PED) in HCC. PED has been shown to regulate cell proliferation, apoptosis and migration in several types of cancer. Howe ...[more]

PMID: 29072691

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Project description:Background & aimsSorafenib is a multireceptor tyrosine kinase inhibitor that can prolong overall survival in patients with advanced hepatocellular carcinoma (HCC). Although most HCC patients who receive sorafenib ultimately show disease progression, it still is unclear whether and how HCC cells acquire chemoresistance during sorafenib treatment in human beings.MethodsWe analyzed surgically resected HCC tissues from a patient who received sorafenib for prevention of HCC recurrence after surgery (Adjuvant Sorafenib for Hepatocellular Carcinoma after Resection or Ablation trial) and established patient-derived HCC cells. Whole-exome sequence analysis was performed to detect mutations in sorafenib-resistant clones. We examined 30 advanced HCC cases immunohistochemically and 140 HCC cases enrolled in the Adjuvant Sorafenib for Hepatocellular Carcinoma after Resection or Ablation trial using microarray analysis to evaluate the association of Capicua Transcriptional Repressor (CIC) status with sorafenib treatment response.ResultsWe found a CIC mutation in recurrent HCC specimens after sorafenib. CIC encodes Capicua, a general sensor of receptor tyrosine kinase signaling. HCC cells established from the recurrent tumor specimen showed chemoresistance to sorafenib in vitro and in vivo. Established sorafenib-resistant Huh1 and Huh7 cell lines showed reduced expression of Capicua without mutations. Immunohistochemical analysis showed that HCC patients with low Capicua expression showed poor overall survival. Microarray analysis showed that the CIC gene signature could predict the preventive effect of adjuvant sorafenib treatment on HCC recurrence. Intriguingly, although CIC knockdown induced sorafenib resistance in HCC cell lines, regorafenib suppressed growth of sorafenib-resistant, Capicua-inactivated HCC cells and inhibited extracellular signal-regulated kinase phosphorylation.ConclusionsEvaluation of Capicua status may be pivotal to predict response to sorafenib, and regorafenib treatment could be effective to treat HCC with functional Capicua impairment.

Project description:BackgroundHepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer-related deaths worldwide. Despite new technologies in diagnosis and treatment, the incidence and mortality of HCC continue rising. And its pathogenesis is still unclear. As a highly conserved protein of the Golgi apparatus, Golgi phosphoprotein 3 (GOLPH3) has been shown to be involved in tumorigenesis of HCC. This study aimed to explore the exact oncogenic mechanism of GOLPH3 and provide a novel diagnose biomarker and therapeutic strategy for patients with HCC.MethodsFirstly, the expression of GOLPH3 was detected in the HCC tissue specimens and HCC cell lines. Secondly, RNA interference was used for GOLPH3 gene inhibition. Thirdly, cell proliferation was analyzed by MTT; cell apoptosis was analyzed by Annexin-V/PI staining, Hoechst 33,342 staining and caspase 3/7 activity assay. Fourthly, xenograft tumor model was used to study the function of GOLPH3 in tumor growth in vivo. Finally, western blotting and immunohistochemistry were used to investigate the role of GOLHP3 in the mTOR signaling pathway.ResultsData showed that the mRNA and protein expression of GOLPH3 were up-regulated in HCC tumor tissue and cell lines compared with those of control (P < 0.05). Correlation analyses showed that GOLPH3 expression was positively correlated with serum alpha-fetoprotein level (AFP, P = 0.006). Knockdown GOLPH3 expression inhibited proliferation and promoted apoptosis in HCC cell lines. What's more, knockdown GOLPH3 expression led to tumor growth restriction in xenograft tumor model. The expression of phosphorylated mTOR, AKT and S6 K1 were significantly higher in HCC tumor tissue and cell lines compared with those in normal liver tissues (p < 0.05). While the phosphorylated mTOR, AKT and S6 K1 were much lower when diminished GOLPH3 expression in HCC cell lines both in vitro and in vivo.ConclusionThe current study suggests that GOLPH3 contributes to the tumorigenesis of HCC by activating mTOR signaling pathway. GOLPH3 is a promising diagnose biomarker and therapeutic target for HCC. Our study may provide a scientific basis for developing effective approaches to treat the HCC patients with GOLPH3 overexpression.

Dataset Information

Phosphoprotein enriched in diabetes (PED/PEA15) promotes migration in hepatocellular carcinoma and confers resistance to sorafenib.

Publications

Phosphoprotein enriched in diabetes (PED/PEA15) promotes migration in hepatocellular carcinoma and confers resistance to sorafenib.

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