Metformin suppresses IL‐22 induced hepatocellular carcinoma by upregulating Hippo signaling pathway

2021 ◽  
Author(s):  
Dong Zhao ◽  
Lei Xia ◽  
Wei Geng ◽  
Dongwei Xu ◽  
Chengpeng Zhong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway

scholarly journals CRISPR Loss-of-Function Screen Identifies the Hippo Signaling Pathway as the Mediator of Regorafenib Efficacy in Hepatocellular Carcinoma

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1362 ◽  
Author(s):  
Shigeki Suemura ◽  
Takahiro Kodama ◽  
Yuta Myojin ◽  
Ryoko Yamada ◽  
Minoru Shigekawa ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Hepatoma Cell ◽  
Hippo Signaling ◽  
Sequencing Analysis ◽  
Loss Of Function ◽  
Hippo Signaling Pathway ◽  
Guide Rnas ◽  
Ic50 Values ◽  
Hcc Cells

Regorafenib is used for hepatocellular carcinoma (HCC), but its response does not last long, partly due to chemoresistance acquisition. We performed a clustered regularly interspaced short palindromic repeats (CRISPR)-based loss-of-function genetic screen and aimed to discover molecules involved in regorafenib resistance in HCC. Xenograft tumors established from Cas9-expressing HCC cells with pooled CRISPR kinome libraries were treated with regorafenib or a vehicle. Sequencing analysis identified 31 genes, with the abundance of multiple guide RNAs increased in regorafenib-treated tumors compared to that in vehicle-treated tumors, including 2 paralogues, LATS2 and LATS1, core components of the Hippo signaling pathway. Notably, all eight designed guide RNAs targeting LATS2 increased in regorafenib-treated tumors, suggesting that LATS2 deletion confers regorafenib resistance in HCC cells. LATS2 knockdown significantly mitigated the cytotoxic and proapoptotic effects of regorafenib on HCC cells. LATS2 inhibition stabilized the Hippo signaling mediator YAP, leading to the upregulation of antiapoptotic Bcl-xL and the multidrug resistance transporter ABCB1. Among 12 hepatoma cell lines, the half maximal inhibitory concentration (IC50) values of regorafenib were positively correlated with any of YAP, Bcl-xL and ABCB1 levels. The inhibition of YAP or Bcl-xL in regorafenib-insensitive HCC cells restored their susceptibility to regorafenib. In conclusion, our screen identified the Hippo signaling pathway as the mediator of regorafenib efficacy in HCC.

c-Src promotes the growth and tumorigenesis of hepatocellular carcinoma via the Hippo signaling pathway

Life Sciences ◽  
2021 ◽  
Vol 264 ◽  
pp. 118711
Author(s):  
Jing Yang ◽  
Xiujuan Zhang ◽  
Leilei Liu ◽  
Xin Yang ◽  
Qingfu Qian ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway

scholarly journals Targeting tumor microenvironment: Metformin suppresses IL-22 induced hepatocellular carcinoma by upregulating Hippo signaling pathway

2020 ◽  
Author(s):  
Dong Zhao ◽  
Tao Zhou ◽  
Yi Luo ◽  
Chenchen Wang ◽  
Dongwei Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Hippo Pathway ◽  
Ectopic Expression ◽  
Tumor Development ◽  
Migration And Invasion ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway

Abstract BackgroundEpidemiological studies have shown direct associations between type 2 diabetes and the risk of cancers. Accumulating evidence indicates that metformin is profoundly implicated in preventing tumor development. However, the exact mechanism underlying the anti-tumor effects of metformin in hepatocellular carcinoma (HCC) is still not clear. MethodsIn this study, we investigated the effects of metformin on a mouse hepatocellular carcinoma (HCC) model and interleukin-22 (IL-22)-associated carcinogenesis in vitro.ResultsWe found that metformin significantly suppressed the incidence and tumor burden of HCC in the diethyl-nitrosamine (DEN)-induced HCC mouse model. As expected, expression of IL-22, an important factor involved in HCC progression, was markedly reduced by metformin. Treatment of HCC cells with metformin inhibited IL-22 induced cell proliferation, migration and invasion, and promoted cell apoptosis. Furthermore, ectopic expression of IL-22 makes HCC more aggressive whereas metformin largely compromised it in vitro and in vivo. Mechanistically, the whole transcriptome analysis and functional analysis revealed that Hippo signaling pathway was involved in the anti-tumor ability of metformin. Consistent with this, metformin directly activated Mst1/2, phosphorylated YAP1 in vitro. After blocking Hippo pathway by XMU-MP-1, the inhibitor of MST1/2, the inhibitory effects by metformin were dramatically attenuated as shown by in vitro study.ConclusionsCollectively, our findings illuminate a new regulatory mechanism, metformin activates Hippo signaling pathway to regulate IL-22 mediated HCC progression and provide new insights into its tumor-suppressive roles.

scholarly journals A novel mitochondrial amidoxime reducing component 2 is a favorable indicator of cancer and suppresses the progression of hepatocellular carcinoma by regulating the expression of p27

Oncogene ◽  
2020 ◽  
Vol 39 (38) ◽  
pp. 6099-6112
Author(s):  
Dehai Wu ◽  
Yan Wang ◽  
Guangchao Yang ◽  
Shugeng Zhang ◽  
Yao Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Tumor Grade ◽  
The United States ◽  
Clinicopathological Characteristics ◽  
In Vivo Studies ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway

Abstract Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related mortality in the United States. Exploring the mechanism of HCC and identifying ideal targets is critical. In the present study, we demonstrated metabolism dysfunction might be a key diver for the development of HCC. The mitochondrial amidoxime reducing component 2 (MARC2) as a newly discovered molybdenum enzyme was downregulated in human HCC tissues and HCC cells. Downregulated MARC2 was significantly associated with clinicopathological characteristics of HCC, such as tumor size, AFP levels, and tumor grade and was an independent risk factor of poor prognosis. Both in vitro and in vivo studies suggested that MARC2 suppressed the progression of HCC by regulating the protein expression level of p27. The Hippo signaling pathway and RNF123 were required for this process. Moreover, MARC2 regulated expression of HNF4A via the Hippo signaling pathway. HNF4A was recruited to the promoter of MARC2 forming a feedback loop. MARC2 levels were downregulated by methylation. We demonstrated the prognostic value of MARC2 in HCC and determined the mechanism by which MARC2 suppressed the progression of HCC in this study. These findings may lead to new therapeutic targets for HCC.

scholarly journals Targeting Tumor Microenvironment: Metformin Suppresses IL-22 Induced Hepatocellular Carcinoma by Upregulating Hippo Signalling Pathway.

2020 ◽  
Author(s):  
Dong Zhao ◽  
Tao Zhou ◽  
Yi Luo ◽  
Chenchen Wang ◽  
Dongwei Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Ectopic Expression ◽  
Tumor Development ◽  
In Vitro Study ◽  
Migration And Invasion ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway

Abstract Background: Epidemiological studies have shown direct associations between type 2 diabetes and the risk of cancers. Accumulating evidence indicates that metformin is profoundly implicated in preventing tumor development. However, the exact mechanism underlying the anti-tumor effects of metformin in hepatocellular carcinoma (HCC) is still not clear. Methods: In this study, we investigated the effects of metformin on a mouse hepatocellular carcinoma (HCC) model and interleukin-22 (IL-22)-associated carcinogenesis in vitro. Results: We found that metformin significantly suppressed the incidence and tumor burden of HCC in the diethyl-nitrosamine (DEN)-induced HCC mouse model. As expected, expression of IL-22, an important factor involved in HCC progression, was markedly reduced by metformin. Treatment of HCC cells with metformin inhibited IL-22 induced cell proliferation, migration and invasion, and promoted cell apoptosis. Furthermore, ectopic expression of IL-22 makes HCC more aggressive whereas metformin largely compromised it in vitro and in vivo. Mechanistically, the whole transcriptome analysis and functional analysis revealed that Hippo signaling pathway was involved in the anti-tumor ability of metformin. Consistent with this, metformin directly activated Mst1/2, phosphorylated YAP1 in vitro. After blocking Hippo pathway by XMU-MP-1, the inhibitor of MST1/2, the inhibitory effects by metformin were dramatically attenuated as shown by in vitro study. Conclusions: Collectively, our findings illuminate a new regulatory mechanism, metformin activates Hippo signaling pathway to regulate IL-22 mediated HCC progression and provide new insights into its tumor-suppressive roles.

scholarly journals Hsa_circ_0005273 facilitates breast cancer tumorigenesis by regulating YAP1-hippo signaling pathway

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Xuehui Wang ◽  
Changle Ji ◽  
Jiashu Hu ◽  
Xiaochong Deng ◽  
Wenfang Zheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Potential Biomarker

Abstract Background Circular RNAs (circRNAs), a novel class of endogenous RNAs, have shown to participate in the development of breast cancer (BC). Hsa_circ_0005273 is a circRNA generated from several exons of PTK2. However, the potential functional role of hsa_circ_0005273 in BC remains largely unknown. Here we aim to evaluate the role of hsa_circ_0005273 in BC. Methods The expression level of hsa_circ_0005273 and miR-200a-3p were examined by RT-qPCR in BC tissues and cell lines. The effect of knocking down hsa_circ_0005273 in BC cell lines were evaluated by examinations of cell proliferation, migration and cell cycle. In addition, xenografts experiment in nude mice were performed to evaluate the effect of hsa_circ_0005273 in BC. RNA immunoprecipitation assay, RNA probe pull-down assay, luciferase reporter assay and fluorescence in situ hybridization were conducted to confirm the relationship between hsa_circ_0005273, miR-200a-3p and YAP1. Results Hsa_circ_0005273 is over-expressed in BC tissues and cell lines, whereas miR-200a-3p expression is repressed. Depletion of hsa_circ_0005273 inhibited the progression of BC cells in vitro and in vivo, while overexpression of hsa_circ_0005273 exhibited the opposite effect. Importantly, hsa_circ_0005273 upregulated YAP1 expression and inactivated Hippo pathway via sponging miR-200a-3p to promote BC progression. Conclusions Hsa_circ_0005273 regulates the miR-200a-3p/YAP1 axis and inactivates Hippo signaling pathway to promote BC progression, which may become a potential biomarker and therapeutic target.

scholarly journals Inhibition of Hippo Signaling Improves Skin Lesions in a Rosacea-Like Mouse Model

2021 ◽  
Vol 22 (2) ◽  
pp. 931
Author(s):  
Jihyun Lee ◽  
Yujin Jung ◽  
Seo won Jeong ◽  
Ga Hee Jeong ◽  
Gue Tae Moon ◽  
...  
Keyword(s):  
Mouse Model ◽  
Signaling Pathway ◽  
Normal Skin ◽  
Skin Lesions ◽  
Hippo Signaling ◽  
Vascular Endothelial ◽  
Expression Levels ◽  
Hippo Signaling Pathway ◽  
Endothelial Growth Factor

The Hippo signaling pathway plays a key role in regulating organ size and tissue homeostasis. Hippo and two of its main effectors, yes-associated protein (YAP) and WWTR1 (WW domain-containing transcription regulator 1, commonly listed as TAZ), play critical roles in angiogenesis. This study investigated the role of the Hippo signaling pathway in the pathogenesis of rosacea. We performed immunohistochemical analyses to compare the expression levels of YAP and TAZ between rosacea skin and normal skin in humans. Furthermore, we used a rosacea-like BALB/c mouse model induced by LL-37 injections to determine the roles of YAP and TAZ in rosacea in vivo. We found that the expression levels of YAP and TAZ were upregulated in patients with rosacea. In the rosacea-like mouse model, we observed that the clinical features of rosacea, including telangiectasia and erythema, improved after the injection of a YAP/TAZ inhibitor. Additionally, treatment with a YAP/TAZ inhibitor reduced the expression levels of YAP and TAZ and diminished vascular endothelial growth factor (VEGF) immunoreactivity in the rosacea-like mouse model. Our findings suggest that YAP/TAZ inhibitors can attenuate angiogenesis associated with the pathogenesis of rosacea and that both YAP and TAZ are potential therapeutic targets for patients with rosacea.

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