Antagonizing STK25 Signaling Suppresses the Development of Hepatocellular Carcinoma Through Targeting Metabolic, Inflammatory, and Pro-Oncogenic Pathways

Kurhe, Yeshwant; Caputo, Mara; Cansby, Emmelie; Xia, Ying; Kumari, Sima; Anand, Sumit Kumar; Howell, Brian W.; Marschall, Hanns‐Ulrich; Mahlapuu, Margit

doi:10.1016/j.jcmgh.2021.09.018

Cited by 10 publications

(12 citation statements)

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“…[ 95 ] Interestingly, we found that the genetic ablation of STK25 protects mice against NASH‐driven HCC via reduced hepatocellular apoptosis and lowered compensatory proliferation, by a mechanism that involves the suppression of hepatic lipotoxicity and inactivation of liver signal transducer and activator of transcription 3 (STAT3), extracellular signal‐regulated kinase 1/2 (ERK1/2), and p38 signaling—the key pathways implicated in human HCC (Figure 5). [ 96 ] In line with these observations, short hairpin RNA knockdown of STK25 has been demonstrated to inhibit tumor growth in human HCC xenografts in nude mice. [ 97 ] The silencing of STK25 also suppresses proliferation, migration, and invasion in human hepatocarcinoma cells in vitro , which is accompanied by a lower expression of the markers of epithelial–mesenchymal transition (EMT) and augmented autophagic flux.…”

Section: Role Of Gckiii Kinases In Hccmentioning

confidence: 87%

“…[ 97 ] The silencing of STK25 also suppresses proliferation, migration, and invasion in human hepatocarcinoma cells in vitro , which is accompanied by a lower expression of the markers of epithelial–mesenchymal transition (EMT) and augmented autophagic flux. [ 96,97 ] Furthermore, high STK25 expression was found to be correlated with adverse clinicopathological characteristics and poor survival in patients with HCC. [ 97 ]…”

Section: Role Of Gckiii Kinases In Hccmentioning

confidence: 99%

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GCKIII kinases in lipotoxicity: Roles in NAFLD and beyond

et al. 2022

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Nonalcoholic fatty liver disease (NAFLD) is defined by excessive accumulation of lipid droplets within hepatocytes. The STE20-type kinases comprising the germinal center kinase III (GCKIII) subfamily -MST3, MST4, and STK25 -decorate intrahepatocellular lipid droplets and have recently emerged as critical regulators of the initiation and progression of NAFLD. While significant advancement has been made toward deciphering the role of GCKIII kinases in hepatic fat accumulation (i.e., steatosis) as well as the aggravation of NAFLD into its severe form nonalcoholic steatohepatitis (NASH), much remains to be resolved. This review provides a brief overview of the recent studies in patient cohorts, cultured human cells, and mouse models, which have characterized the function of MST3, MST4, and STK25 in the regulation of hepatic lipid accretion, meta-inflammation, and associated cell damage in the context of NAFLD/NASH. We also highlight the conflicting data and emphasize future research directions that are needed to advance our understanding of GCKIII kinases as potential targets in the therapy of NAFLD and its comorbidities. Conclusions: Several lines of evidence suggest that GCKIII proteins govern the susceptibility to hepatic lipotoxicity and that pharmacological inhibition of these kinases could mitigate NAFLD development and aggravation. Comprehensive characterization of the molecular mode-of-action of MST3, MST4, and STK25 in hepatocytes as well as extrahepatic tissues is important, especially in relation to their impact on carcinogenesis, to fully understand the efficacy as well as safety of GCKIII antagonism.

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Section: Role Of Gckiii Kinases In Hccmentioning

confidence: 87%

Section: Role Of Gckiii Kinases In Hccmentioning

confidence: 99%

GCKIII kinases in lipotoxicity: Roles in NAFLD and beyond

et al. 2022

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“…DEN is a carcinogen that has been used to induce HCC in different laboratory animal species. [53][54][55] We have previously used DEN in miniature pigs, and found that the histopathological features of the developed HCC resemble to a great extent the human neoplasm. 56 Although etiologically DEN-induced HCC does not mimic this type of cancer in human patients, this model has several important pathological, histological, and biochemical similarities with human HCC.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Growth Hormone Receptor Signaling Abrogates Hepatocellular Carcinoma Development

Haque¹,

Sahu²,

Lombardo³

et al. 2022

JHC

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Introduction Hepatocellular carcinoma (HCC) is the most common type of primary liver cancers. It is an aggressive neoplasm with dismal outcome because most of the patients present with an advanced-stage disease, which precludes curative surgical options. Therefore, these patients require systemic therapies that typically induce small improvements in overall survival. Hence, it is crucial to identify new and promising therapeutic targets for HCC to improve the current outcome. The liver is a key organ in the signaling cascade triggered by the growth hormone receptor (GHR). Previous studies have shown that GHR signaling stimulates the proliferation and regeneration of liver cells and tissues; however, a definitive role of GHR signaling in HCC pathogenesis has not been identified. Methods In this study, we used a direct and specific approach to analyze the role of GHR in HCC development. This approach encompasses mice with global ( Ghr −/− ) or liver-specific ( LiGhr −/− ) disruption of GHR expression, and the injection of diethylnitrosamine (DEN) to develop HCC in these mice. Results Our data show that DEN induced HCC in a substantial majority of the Ghr +/+ (93.5%) and Ghr +/- (87.1%) mice but not in the Ghr −/− (5.6%) mice (P < 0.0001). Although 57.7% of LiGhr −/− mice developed HCC after injection of DEN, these mice had significantly fewer tumors than LiGhr +/+ (P < 0.001), which implies that the expression of GHR in the liver cells might increase tumor burden. Notably, the pathologic, histologic, and biochemical characteristics of DEN-induced HCC in mice resembled to a great extent human HCC, despite the fact that etiologically this model does not mimic this cancer in humans. Our data also show that the effects of DEN on mice livers were primarily related to its carcinogenic effects and ability to induce HCC, with minimal effects related to toxic effects. Conclusion Collectively, our data support an important role of GHR in HCC development, and suggest that exploiting GHR signaling may represent a promising approach to treat HCC.

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“…Cell metastasis is one of cancer cells process occurring when primary tumor spread through lymphatic and circulatory system to the nearest organs, as well as is reported to be responsible for over 90% of cancer deaths. Cell migration (motility) is a critical cause of tissue invasion supporting primary tumors to disseminate and metastasize 8 – 10 . Collective cell migration is mediated by coordinate cytoskeletal activity with cell–cell interaction with neighbor cells and surrounds.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, liver cancer has been grouping into five stages to prevent medical intervention harms in patients with cirrhosis. Liver cancer metastasis appears in fourth of five stages classify as advanced stage, indicating that the cancer could spread from origin to other organs 8 . For explanation, metastasis occurs when the primary cancer travels from its original place through the bloodstream and lymph node, then forms a secondary or metastatic tumor in the nearest organs.…”

Section: Introductionmentioning

confidence: 99%

Bioactive xanthones, benzophenones and biphenyls from mangosteen root with potential anti-migration against hepatocellular carcinoma cells

Choodej

Koopklang

Raksat

et al. 2022

Sci Rep

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Liver cancer refers primarily to hepatocellular carcinoma (HCC) accounting for over 90% of cases and is the highest incidence in men in Thailand. Over the past decades, the incidence of HCC dramatically increased with a strong rise of mortality rates. Garcinia mangostana, “Queen of Fruit” of Thailand, is known as a rich source of xanthones with potent cytotoxic properties against various cancer cells. Study on xanthones is provoking not only due to the structural diversity but also a wide variety of pharmacological activities. Hence the aim of the current study is to determine the effects of metabolites from G. mangostana root on cell proliferation and migration of hepatocellular carcinoma cells. Twenty-two metabolites, including two new benzophenones and one new biphenyl, were isolated and characterized. Five xanthones with a prenyl moiety showed significant cytotoxicity against both HCC cells tested; however, only dulxanthone D displayed the most promising activity on the migration of Huh7 HCC cells, comparable to sorafenib, a standard drug. Moreover, the compound dose-dependently induced apoptosis in Huh7 cells via mitochondrial pathway. Accordingly, dulxanthone D held a great potential for development as a novel migration inhibitor for effective HCC treatment.

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Antagonizing STK25 Signaling Suppresses the Development of Hepatocellular Carcinoma Through Targeting Metabolic, Inflammatory, and Pro-Oncogenic Pathways

Cited by 10 publications

References 57 publications

GCKIII kinases in lipotoxicity: Roles in NAFLD and beyond

GCKIII kinases in lipotoxicity: Roles in NAFLD and beyond

Disruption of Growth Hormone Receptor Signaling Abrogates Hepatocellular Carcinoma Development

Bioactive xanthones, benzophenones and biphenyls from mangosteen root with potential anti-migration against hepatocellular carcinoma cells

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