Complex roles of Hippo-YAP/TAZ signaling in hepatocellular carcinoma.

BACKGROUND: The Hippo signaling pathway is an evolutionarily conserved signaling module that controls organ size in different species, and the disorder of the Hippo pathway can induce liver cancer in organisms, especially hepatocellular carcinoma (HCC). The exact mechanism that causes cancer is still unknown. Recent studies have shown that it is a classical kinase cascade that phosphorylates the Mst1/2-sav1 complex and activates the phosphorylation of the Lats1/2-mob1A/B complex for inactivating Yap and Taz. These kinases and scaffolds are regarded as primary regulators of the Hippo pathway, and help in activating a variety of carcinogenic processes. Among them, Yap/Taz is seen to be the main effector molecule, which is downstream of the Hippo pathway, and its abnormal activation is related to a variety of human cancers including liver cancer. Currently, since Yap/Taz plays a variety of roles in cancer promotion and tumor regeneration, the Hippo pathway has emerged as an attractive target in recent drug development research. METHODS: We collect and review relevant literature in web of Science and Pubmed. CONCLUSION: This review highlights the important roles of Yap/Taz in activating Hippo pathway in liver cancer. The recent findings on the crosstalks between the Hippo and other cancer associated pathways and moleculars are also discussed. In this review, we summarized and discussed recent breakthroughs in our understanding of how key components of the Hippo-YAP/TAZ pathway influence the hepatocellular carcinoma, including their effects on tumor occurrence and development, their roles in regulating metastasis, and their function in chemotherapy resistance. Further, the molecular mechanism and roles in regulating cross talk between Hippo-YAP/TAZ pathway and other cancer-associated pathways or oncogenes/cancer suppressor genes were summarized and discussed. More, many other inducers and inhibitors of this signaling cascade and available experimental therapies against the YAP/TAZ/TEAD axis were discussed. Targeting this pathway for cancer therapy may have great significance in the treatment of hepatocellular carcinoma. Graphical summary of the complex role of Hippo-YAP/TAZ signaling in hepatocellular carcinoma.

The abrogation of GRP78 sensitizes liver cancer cells to lysionotin by enhancing ER stress-mediated pro-apoptotic pathway.

Glucose-regulated protein 78 (GRP78) is frequently and highly expressed in various human malignancies and protects cancer cells against apoptosis induced by multifarious stresses, particularly endoplasmic reticulum stress (ER stress). The inhibition of GRP78 expression or activity could enhance apoptosis induced by anti-tumor drugs or compounds. Herein, we will evaluate the efficacy of lysionotin in the treatment of human liver cancer as well as the molecular mechanism. Moreover, we will examine whether inhibition of GRP78 enhanced the sensitivity of hepatocellular carcinoma cells to lysionotin. We found that lysionotin significantly suppressed proliferation and induced apoptosis of liver cancer cells. TEM showed that lysionotin-treated liver cancer cells showed an extensively distended and dilated endoplasmic reticulum lumen. Meanwhile, the levels of the ER stress hallmark GRP78 and UPR hallmarks (e.g., IRE1α and CHOP) were significantly increased in response to lysionotin treatment in liver cancer cells. Moreover, the reactive oxygen species (ROS) scavenger NAC and caspase-3 inhibitor Ac-DEVD-CHO visibly attenuated the induction of GRP78 and attenuated the decrease in cell viability induced by lysionotin. More importantly, the knockdown of GRP78 expression by siRNAs or treatment with EGCG, both induced remarkable increase in lysionotin-induced PARP and pro-caspase-3 cleavage and JNK phosphorylation. In addition, knockdown of GRP78 expression by siRNA or suppression GRP78 activity by EGCG both significantly improved the effectiveness of lysionotin. These data indicated that pro-survival GRP78 induction may contribute to lysionotin resistance. The combination of EGCG and lysionotin is suggested to represent a novel approach in cancer chemo-prevention and therapeutics.

Activating the Hippo pathway by nevadensin overcomes Yap-drived resistance to sorafenib in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly malignant type of tumor that is insensitive to cytotoxic chemotherapy and often develops drug resistance. Nevadensin, a bioflavonoid, exhibits anti-cancer properties in some cancers. However, the precise underlying mechanism of nevadensin against liver cancer are poorly understood. We aim to evaluate the efficacy as well as the molecular mechanism of nevadensin in the treatment of liver cancer. METHODS: Effects of nevadensin on HCC cell proliferation and apoptosis were detected using EdU labeling and flow cytometry assays. The molecular mechanism of nevadensin on HCC was determined using RNAseq. The effects of nevadensin on hippo-Yap signaling were verified using western blot and RT-PCR. RESULTS: In this study, we show that nevadensin significantly inhibits growth of HCC cells via inducing cell cycle arrest and apoptosis. RNAseq analysis showed that nevadensin regulates multiple functional signaling pathways associated with cancer including Hippo signaling. Western Blot analysis revealed that nevadensin notably induces activation of the MST1/2- LATS1/2 kinase in HCC cells, further resulting in the primary effector molecule YAP phosphorylation and subsequent degradation. These results indicated that nevadensin might exert its anti-HCC activity through the Hippo-ON mechanism. Moreover, nevadensin could increase the sensitivity of HCC cells to sorafenib by down-regulating YAP and its downstream targets. CONCLUSIONS: The present study indicates that nevadensin could be a potential effective approach to treating HCC, and overcoming sorafeni resistance via inducing activation of Hippo signaling.

CLDN4 promotes growth of acute myeloid leukemia cells via regulating AKT and ERK1/2 signaling.

Acute myeloid leukemia (AML) is the most common acute leukemia affecting adults. The tight junction protein CLDN4 is closely related to the development of various epithelial cell carcinomas. However, whether CLDN4 contributes to AML development remains unclear. For the first time, we found that expression of CLDN4 is aberrantly up-regulated in AML cells. Knockdown of CLDN4 expression resulted in a dramatic decreased cell growth, elevated apoptosis of AML cells. Further, we revealed that knockdown of CLDN4 inhibits mRNA expression of PIK3R3 and MAP2K2, thus suppresses activation of AKT and ERK1/2. More importantly, activating AKT branch by SC79 partially compromised CLDN4 knockdown induced cell viability inhibition. In addition, we found that higher expression of CLDN4 is connected to worse survival and is an independent indicator of shorter disease free survival (DFS) in AML patients. Together, our results indicate that CLDN4 contributes to AML pathogenesis, and suggests that targeting CLDN4 is a promising option for AML treatment.