Sharpin promotes hepatocellular carcinoma progression via transactivation of Versican expression

Tanaka, Yasuo; Tateishi, Keisuke; Nakatsuka, Takuma; Kudo, Yotaro; Takahashi, Ryōsuke; Miyabayashi, Koji; Yamamoto, Keisuke; Asaoka, Yoshinari; Ijichi, Hideaki; Tateishi, Ryosuke; Shibahara, Junji; Fukayama, Masashi; Ishizawa, Toshihiro; Hasegawa, Kiyoshi; Kokudo, Norihiro; Koike, Kazuhiko

doi:10.1038/oncsis.2016.76

Cited by 30 publications

(34 citation statements)

References 31 publications

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“…Upregulation of SHARPIN in HCC [22] was confirmed in a previous study by our group [25] , in which SHARPIN expression was shown to be positively correlated with larger hepatic tumors, a higher histological grade, and therefore HCC progression. In recently published work, we examined the role of SHARPIN in the malignant phenotype characteristic of HCC [25] .…”

Section: Sharpin: Newly Identified Mediator Of Hcc Invasion and Progrsupporting

confidence: 66%

“…Its expression is significantly higher in HCC and is correlated positively with SHARPIN expression. Knockdown of versican attenuates HCC invasion, which implicates versican in SHARPIN-mediated HCC invasion, and this relationship was confirmed in an in vivo tumor model [25] . Versican transcription is regulated by T-cell factor (TCF) [28][29] .…”

Section: Sharpin: Newly Identified Mediator Of Hcc Invasion and Progrmentioning

confidence: 61%

“…Versican transcription is regulated by T-cell factor (TCF) [28][29] . Our group relatedly showed that SHARPIN, via its NZF domain, induces significant versican promoter activity and consequently versican expression [25] . Mutation of the versican promoter at its putative TCF/lymphoid enhancer factor (LEF) binding site prevented promoter activation by SHARPIN, suggesting involvement of the Wnt/β-catenin pathway, a key signaling pathway in embryonic development and tissue homeostasis.…”

Section: Sharpin: Newly Identified Mediator Of Hcc Invasion and Progrmentioning

confidence: 96%

“…In recently published work, we examined the role of SHARPIN in the malignant phenotype characteristic of HCC [25] . Although SHARPIN does not seem to play a significant role in cell growth, its overexpression has been linked to significantly higher rates of cell invasion.…”

Section: Sharpin: Newly Identified Mediator Of Hcc Invasion and Progrmentioning

confidence: 99%

“…In addition, the NZF domain of SHARPIN was shown to be indispensable for HCC invasion. The molecular mechanism of SHARPIN-induced cell invasion was examined by cDNA microarray analysis, which demonstrated upregulation of versican in SHARPIN-expressing cells [25] . Versican is an aggregating chondroitin sulfate proteoglycan expressed mainly in the ECM; it is critical to the maintenance of tissue integrity and homeostasis.…”

Section: Sharpin: Newly Identified Mediator Of Hcc Invasion and Progrmentioning

confidence: 99%

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Emerging role of SHARPIN in hepatocellular carcinoma progression

Tanaka

Tateishi²,

Koike³

2017

Can Cell Microenviron

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Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and the leading cause of cancer-related death, especially in less economically developed regions. Despite recent progress in the diagnosis and therapy of HCC, the long-term survival rate of HCC patients is unacceptably low, in part due to the frequent development of vascular invasion or distant metastasis. The cellular functions of shank-associated RH domain-interacting protein (SHARPIN, also known as SIPL1) include the regulation of inflammation, apoptosis, immune signaling, and cell motility. SHARPIN is up-regulated in various types of cancers including HCC and has been implicated in the genesis and progression of malignant tumors, but its exact role in tumorigenesis is largely unknown. Here we present evidence supporting a role for SHARPIN in HCC invasion and progression. We also discuss the potential of SHARPIN and related genes as therapeutic targets for this currently incurable cancer.

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Section: Sharpin: Newly Identified Mediator Of Hcc Invasion and Progrsupporting

confidence: 66%

Section: Sharpin: Newly Identified Mediator Of Hcc Invasion and Progrmentioning

confidence: 61%

Section: Sharpin: Newly Identified Mediator Of Hcc Invasion and Progrmentioning

confidence: 96%

Section: Sharpin: Newly Identified Mediator Of Hcc Invasion and Progrmentioning

confidence: 99%

Section: Sharpin: Newly Identified Mediator Of Hcc Invasion and Progrmentioning

confidence: 99%

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Emerging role of SHARPIN in hepatocellular carcinoma progression

Tanaka

Tateishi²,

Koike³

2017

Can Cell Microenviron

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Versican in the Tumor Microenvironment

Papadas

Asimakopoulos

2020

Advances in Experimental Medicine and Biology

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SHARPIN stabilizes β-catenin through a linear ubiquitination-independent manner to support gastric tumorigenesis

Zhang

Liu

et al. 2020

Gastric Cancer

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Background Aberrant activation of Wnt/β-catenin signaling by dysregulated post-translational protein modifications, especially ubiquitination is causally linked to cancer development and progression. Although Lys48-linked ubiquitination is known to regulate Wnt/β-catenin signaling, it remains largely obscure how other types of ubiquitination, such as linear ubiquitination governs its signaling activity. Methods The expression and regulatory mechanism of linear ubiquitin chain assembly complex (LUBAC) on Wnt/β-catenin signaling was examined by immunoprecipitation, western blot and immunohistochemical staining. The ubiquitination status of β-catenin was detected by ubiquitination assay. The impacts of SHARPIN, a core component of LUBAC on malignant behaviors of gastric cancer cells were determined by various functional assays in vitro and in vivo. Results Unlike a canonical role in promoting linear ubiquitination, SHARPIN specifically interacts with β-catenin to maintain its protein stability. Mechanistically, SHARPIN competes with the E3 ubiquitin ligase β-Trcp1 for β-catenin binding, thereby decreasing β-catenin ubiquitination levels to abolish its proteasomal degradation. Importantly, SHARPIN is required for invasiveness and malignant growth of gastric cancer cells in vitro and in vivo, a function that is largely dependent on its binding partner β-catenin. In line with these findings, elevated expression of SHARPIN in gastric cancer tissues is associated with disease malignancy and correlates with β-catenin expression levels. Conclusions Our findings reveal a novel molecular link connecting linear ubiquitination machinery and Wnt/β-catenin signaling via SHARPIN-mediated stabilization of β-catenin. Targeting the linear ubiquitination-independent function of SHARPIN could be exploited to inhibit the hyperactive β-catenin signaling in a subset of human gastric cancers.

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Sharpin promotes hepatocellular carcinoma progression via transactivation of Versican expression

Cited by 30 publications

References 31 publications

Emerging role of SHARPIN in hepatocellular carcinoma progression

Emerging role of SHARPIN in hepatocellular carcinoma progression

Versican in the Tumor Microenvironment

SHARPIN stabilizes β-catenin through a linear ubiquitination-independent manner to support gastric tumorigenesis

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