Sestrin 2 confers primary resistance to sorafenib by simultaneously activating AKT and AMPK in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the malignancy derived from normal hepatocytes with increasing incidence and extremely poor prognosis worldwide. The only approved first-line systematic treatment agent for HCC, sorafenib, is capable to effectively improve advanced HCC patients' survival. However, it is gradually recognized that the therapeutic response to sorafenib could be drastically diminished after short-term treatment, defined as primary resistance. The present study is aimed to explore the role of stress-inducible protein Sestrin2 (SESN2), one of the most important sestrins family members, in sorafenib primary resistance. Herein, we initially found that SESN2 expression was significantly up-regulated in both HCC cell lines and tissues compared to normal human hepatocytes and corresponding adjacent liver tissues, respectively. In addition, SESN2 expression was highly correlated with sorafenib IC50 of HCC cell lines. Thereafter, we showed that sorafenib treatment resulted in an increase of SESN2 expression and the knockdown of SESN2 exacerbated sorafenib-induced proliferation inhibition and cell apoptosis. Further mechanistic study uncovered that SESN2 deficiency impaired both AKT and AMPK phosphorylation and activation after sorafenib treatment. Moreover, the correlations between SESN2 expression and both phosphor-AKT and phosphor-AMPK expression were illustrated in HCC tissues. Taken together, our study demonstrates that SESN2 activates AKT and AMPK signaling as a novel mechanism to induce sorafenib primary resistance in HCC.

Dai J ，Huang Q ，Niu K ，Wang B ，Li Y ，Dai C ，Chen Z ，Tao K ，Dai J ... -  《Cancer Medicine》

[Sestrin 2(SESN2) promotes primary resistance to sorafenib by activating AKT in hepatocellular carcinoma cells].

Dai J ，Niu K ，Wang B ，Li Y ，Xia C ，Tao K ，Dai J ... -  《-》

SETD1A augments sorafenib primary resistance via activating YAP in hepatocellular carcinoma.

Sorafenib, the approved first-line chemotherapy drug for HCC (Hepatocellular Carcinoma), remains the key treatment agent which effectively improves the survival rate of advanced HCC patients. However, the sorafenib primary resistance limits the application of sorafenib for HCC treatment. The aims of current study are to explore the role and mechanism of SETD1A (Histone Lysine Methyltransferase SET Domain Containing 1A) in sorafenib primary resistance. The SETD1A expression in HCC was analyzed by Gene Expression Profiling Interactive Analysis. The survival of HCC patients was analyzed by Kaplan-Meier Plotter. Western Blot and Real-time qPCR were performed to measure the protein and mRNA levels, respectively. Cell counting kit-8 assay and colony formation assay were performed to determine cell viability and proliferation. Propidium Iodide and Trypan Blue staining assays were performed to investigate cell death. Here, we showed that the expression of SETD1A was markedly upregulated in both HCC cell lines and tumor tissues compared to normal hepatocytes and corresponding non-tumor liver tissues, respectively. Regardless of whether treated with sorafenib, the patients who had higher level of SETD1A underwent lower survival rate of overall. In addition, SETD1A expression was positively correlated with the IC50 of sorafenib treated HCC cell lines. Furthermore, we indicated that knockdown of SETD1 augmented proliferation inhibition and cell death induced by sorafenib. SETD1A deficiency impaired YAP (Yes-associated protein) phosphorylation and activation. YAP activation contributed to SETD1A mediated sorafenib primary resistance. The current study demonstrated that SETD1A enhanced YAP activation to induce sorafenib primary resistance in HCC.

Wu J ，Chai H ，Li F ，Ren Q ，Gu Y ... -  《-》

ID1-induced p16/IL6 axis activation contributes to the resistant of hepatocellular carcinoma cells to sorafenib.

Niu LL ，Cheng CL ，Li MY ，Yang SL ，Hu BG ，Chong CCN ，Chan SL ，Ren J ，Chen GG ，Lai PBS ... -  《-》

IGF2 Is Up-regulated by Epigenetic Mechanisms in Hepatocellular Carcinomas and Is an Actionable Oncogene Product in Experimental Models.

Martinez-Quetglas I ，Pinyol R ，Dauch D ，Torrecilla S ，Tovar V ，Moeini A ，Alsinet C ，Portela A ，Rodriguez-Carunchio L ，Solé M ，Lujambio A ，Villanueva A ，Thung S ，Esteller M ，Zender L ，Llovet JM ... -  《-》