A genetic variant in large tumor suppressor kinase 2 of Hippo signaling pathway contributes to prognosis of hepatocellular carcinoma

Abstract Apoptosis signal-regulating kinase 1 (ASK1) is an important mediator of the cell stress response pathways. Because of its central role in regulating cell death, the activity of ASK1 is tightly regulated by protein–protein interactions and post-translational modifications. Deregulation of ASK1 activity has been linked to human diseases, such as neurological disorders and cancer. Here we describe the identification and characterization of large tumor suppressor 2 (LATS2) as a novel binding partner for ASK1. LATS2 is a core kinase in the Hippo signaling pathway and is commonly downregulated in cancer. We found that LATS2 interacts with ASK1 and increases ASK1-mediated signaling to promote apoptosis and activate the JNK mitogen-activated protein kinase (MAPK). This change in MAPK signaling is dependent on the catalytic activity of ASK1 but does not require LATS2 kinase activity. This work identifies a novel role for LATS2 as a positive regulator of the ASK1–MKK–JNK signaling pathway and establishes a kinase-independent function of LATS2 that may be part of the intricate regulatory system for cellular response to diverse stress signals.

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Macrophage-Derived Exosomal miR-31-5p Promotes Oral Squamous Cell Carcinoma Tumourigenesis Through the Large Tumor Suppressor 2-Mediated Hippo Signalling Pathway

Journal of Biomedical Nanotechnology ◽

10.1166/jbn.2021.3066 ◽

2021 ◽

Vol 17 (5) ◽

pp. 822-837

Author(s):

Yi Yuan ◽

Zeyu Wang ◽

Mengqi Chen ◽

Yang Jing ◽

Wei Shu ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Tumor Suppressor ◽

Oral Squamous Cell Carcinoma ◽

M2 Macrophage ◽

Hippo Signaling ◽

M2 Macrophages ◽

Large Tumor ◽

Hippo Signaling Pathway ◽

Exosomal Mirnas ◽

Large Tumor Suppressor

Tumour-associated macrophages (TAMs) are thought to contribute to oral squamous cell carcinoma (OSCC) initiation and progression. However, the underlying mechanism through which TAMs foster OSCC progression is still unclear. This study intended to determine whether there are exclusively exosomal miRNAs-derived macrophages that are functionally necessary for OSCC progression. The phenotype of TAM recruitment in OSCC tissue samples was assessed, subsequently identifying the influence of M2 macrophages and exosomes derived from M2 macrophages on OSCC proliferation and tumorigenesis in vitro and in vivo. CD68 and CD163, the specific markers of M2 type macrophages, were upregulated in TAMs presented in intra-cancer tissues. M2 macrophages and M2 macrophage-derived exosomes (M2 exos) both can promote OSCC growth and tumorigenicity. An exosomal RNA-seq analysis was conducted to predict regulatory exosomal miRNAs related to OSCC growth, which determined miR-31-5p and LATS2 for subsequent experiments. Mechanistically, miR-31-5p was delivered to recipient OSCC cells through M2 exos and complementary pairing with the large tumor suppressor 2 (LATS2) coding sequence, thus suppressing the expression of LATS2 and inactivation the Hippo signaling pathway to support OSCC growth. Collectively, our findings demonstrate that M2 macrophage-derived exosomal miR- 31-5p can make tumor suppressor LATS2 gene inhibited and facilitate the progression of OSCC via inhibiting the Hippo signaling pathway, which possibly provides new targets for the molecular therapy of OSCC.

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Dual Role of a C-Terminally Truncated Isoform of Large Tumor Suppressor Kinase 1 in the Regulation of Hippo Signaling and Tissue Growth

DNA and Cell Biology ◽

10.1089/dna.2018.4340 ◽

2019 ◽

Vol 38 (1) ◽

pp. 91-106 ◽

Cited By ~ 1

Author(s):

Yurika Matsui ◽

Yifan Zhang ◽

Robert F. Paulson ◽

Zhi-Chun Lai

Keyword(s):

Tumor Suppressor ◽

Tissue Growth ◽

Dual Role ◽

Hippo Signaling ◽

Large Tumor ◽

Large Tumor Suppressor

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MicroRNA miR-4709-3p targets Large Tumor Suppressor Kinase 2 (LATS2) and induces obstructive renal fibrosis through Hippo signaling

Bioengineered ◽

10.1080/21655979.2021.2002493 ◽

2021 ◽

Vol 12 (2) ◽

pp. 12357-12371

Author(s):

Zexiang Jiang ◽

Weiping Xia ◽

Guoyu Dai ◽

Bo Zhang ◽

Yang Li ◽

...

Keyword(s):

Tumor Suppressor ◽

Renal Fibrosis ◽

Hippo Signaling ◽

Large Tumor ◽

Large Tumor Suppressor

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

Journal of Gastroenterology and Hepatology ◽

10.1111/jgh.15674 ◽

2021 ◽

Author(s):

Dong Zhao ◽

Lei Xia ◽

Wei Geng ◽

Dongwei Xu ◽

Chengpeng Zhong ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Hippo Signaling ◽

Hippo Signaling Pathway

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miR-650 Promotes the Metastasis and Epithelial–Mesenchymal Transition of Hepatocellular Carcinoma by Directly Inhibiting LATS2 Expression

Cellular Physiology and Biochemistry ◽

10.1159/000495495 ◽

2018 ◽

Vol 51 (3) ◽

pp. 1179-1192 ◽

Cited By ~ 10

Author(s):

Li Li Han ◽

Xiao Ran Yin ◽

Shu Qun Zhang

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Suppressor ◽

Epithelial Mesenchymal Transition ◽

Luciferase Assay ◽

Large Tumor ◽

Mesenchymal Transition ◽

Expression Levels ◽

Direct Target ◽

Large Tumor Suppressor ◽

Hcc Cells

Background/Aims: Previous studies have confirmed that microRNAs are involved in the metastasis and epithelial–mesenchymal transition (EMT) of malignancies. In this study, we examined whether miR-650 promotes the migration, invasion, and EMT of hepatocellular carcinoma (HCC) cells by targeting the large tumor suppressor kinase 2 gene (LATS2). Methods: qRT-PCR was used to detect expression of miR-650 in HCC tissues and paired normal tissues. MTT and Transwell assay were used to observe the effect of miR-650 on proliferation, migration and invasion of HCC cells. Western blot assay and Immunohistochemistry were performed to demonstrate association between miR-650 expression level and epithelial-mesenchymal transition (EMT) related protein. Mechanistically, Reporter luciferase assay was performed to reveal whether large tumor suppressor kinase 2 (LATS2) was a direct target of miR-650 in HCC cells. Results: We observed that miR-650 levels were largely up-regulated in HCC tissues, and that the increased expression was closely associated with the adverse clinical features of HCC patients. Additionally, the expression of LATS2, which was identified as a direct target of miR-650, can counteract the effects of miR-650 in HCC. Furthermore, we demonstrated that high miR-650 expression levels and low LATS2 expression levels in tumors may indicate a poor prognosis for HCC patients. Conclusion: In conclusion, the miR-650/LATS2 pathway may serve as a novel prognostic biomarker and an attractive therapeutic target for HCC patients.

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

Cancers ◽

10.3390/cancers11091362 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1362 ◽

Cited By ~ 2

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.

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