Human tetraspanin transmembrane 4 superfamily member 4 or intestinal and liver tetraspan membrane protein is overexpressed in hepatocellular carcinoma and accelerates tumor cell growth

Li, Ying; Wang, Leiming; Qiu, Jie; Da, Liu; Tiollais, Pierre; Li, Zai-Ping; Zhao, Ming

doi:10.1093/abbs/gmr124

Cited by 19 publications

(20 citation statements)

References 23 publications

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“…TSPAN4 and Smoc2 were also upregulated in Shp Ϫ/Ϫ mice and fibrotic liver disease. A recent study showed that TSPAN4 was significantly overexpressed in HCC (22), and Smoc2 potentiates the angiogenic effects of growth factors (35). However, the functions of these genes in liver remain largely unstudied.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide transcriptome analysis identifies novel gene signatures implicated in human chronic liver disease

Smalling

Delker

Zhang

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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The molecular mechanisms behind human liver disease progression to cirrhosis remain elusive. Nuclear receptor small heterodimer partner (SHP/Nr0b2) is a hepatic tumor suppressor and a critical regulator of liver function. SHP expression is diminished in human cirrhotic livers, suggesting a regulatory role in human liver diseases. The goal of this study was to identify novel SHP-regulated genes that are involved in the development and progression of chronic liver disease. To achieve this, we conducted the first comprehensive RNA sequencing (RNA-seq) analysis of Shp(-/-) mice, compared the results with human hepatitis C cirrhosis RNA-seq and nonalcoholic steatohepatitis (NASH) microarray datasets, and verified novel results in human liver biospecimens. This approach revealed new gene signatures associated with chronic liver disease and regulated by SHP. Several genes were selected for validation of physiological relevance based on their marked upregulation, novelty with regard to liver function, and involvement in gene pathways related to liver disease. These genes include peptidoglycan recognition protein 2, dual specific phosphatase-4, tetraspanin 4, thrombospondin 1, and SPARC-related modular calcium binding protein-2, which were validated by qPCR analysis of 126 human liver specimens, including steatosis, fibrosis, and NASH, alcohol and hepatitis C cirrhosis, and in mouse models of liver inflammation and injury. This RNA-seq analysis identifies new genes that are regulated by the nuclear receptor SHP and implicated in the molecular pathogenesis of human chronic liver diseases. The results provide valuable transcriptome information for characterizing mechanisms of these diseases.

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Section: Discussionmentioning

confidence: 99%

Genome-wide transcriptome analysis identifies novel gene signatures implicated in human chronic liver disease

Smalling

Delker

Zhang

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In CCl 4 -induced acute liver injury model in rats, TM4SF4 is also up-regulated in injured livers, and overexpression of TM4SF4 can accelerate liver injury [10]. For humans, TM4SF4 is found to be overexpressed in 70% liver cancer tissues and correlates with tumor progression [11]. Moreover, TM4SF4 can regulate endocrine pancreas differentiation and directed cell migration [12].…”

Section: Introductionmentioning

confidence: 99%

Adenovirus-mediated delivery of siRNA targeting TM4SF4 attenuated liver cancer cell growth <italic>in vitro</italic> and <italic>in vivo</italic>

Wang¹,

Feng²,

Da³

et al. 2013

ABBS

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Gene targeting using short interfering RNA (siRNA) has become a common strategy to explore gene function because of its prominent efficacy and specificity. The human transmembrane 4 superfamily member 4 (TM4SF4) was originally identified in intestine and liver as a cell proliferation-related gene. Recently, it showed an increased expression in the hepatocellular carcinoma (HCC) tissues. In this study, we developed an adenoviral vector harboring an effective siRNA targeting TM4SF4 (AdSiTM4SF4) and identified its function in suppression of tumor cell growth. It was confirmed that TM4SF4 was overexpressed in HCC tissues compared with its paired non-tumor tissues by western blot analysis and immunohistochemistry. Remarkably, it was more abundant on the cell surface of HCC cells. The signals of ectopically expressed TM4SF4 in four cell lines dramatically localized in the plasma membrane, slightly in the cytoplasm, and absent in the nucleus, demonstrating that TM4SF4 is a membrane protein. Targeting TM4SF4 by AdSiTM4SF4 successfully exerted a gene knockdown effect. The QGY-7701 and SMMC-7721 HCC cells infected with AdSiTM4SF4 displayed remarkably attenuated growth potential.Moreover, intratumoral injection of AdSiTM4SF4 significantly suppressed tumor growth in a xenograft mouse model using SMMC-7721 hepatoma cells. Our results indicated that targeting TM4SF4 might be a promising modality for inhibition of HCC.

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“…In contrast to TM4SF1 and TM4SF5, which slightly increased cell proliferation in 2D cell culture condition, TM4SF4 had a slightly decreasing effect on cell growth. TM4SF4 is upregulated in injured liver in CCl 4 -treated mice [11], overexpressed in liver cancer tissues [12, 24], and is correlated with directional migration [16, 25], similar to TM4SF5 [26]. However, controversy surrounds the effects of TM4SF4 on cell growth.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, TM4SF1 in breast cancer cells couples the collagen I receptor tyrosine kinase DDR1 to the syntenin 2, a cortical adaptor, and further PKCα that promotes phosphorylation and activation of JAK2 and STAT3 for cancer stem cell traits and metastatic reactivation in the metastatic sites such as lung, bone, and brain [8]. Meanwhile, TM4SF4 is expressed in non-dividing hepatocytes and upregulated during liver injury possibly for cellular differentiation and regeneration [9–11], although it is highly enhanced in liver cancer [12]. Enhanced TM4SF4 level in lung carcinoma cells can lead to resistance to radiotherapy via IGF1-induced IGFR activation [13].…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of cellular functions by the C-termini of transmembrane 4 L six family proteins in 2- or 3-dimensional environment

Cheong

Song

et al. 2017

Oncotarget

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The transmembrane 4 L six family proteins TM4SF1, TM4SF4, and TM4SF5 share 40-50% overall sequence identity, but their C-terminus identity is limited. It may be likely that the C-termini of the members are important and unique for own regulatory functions. We thus examined how the TM4SF5 C-terminus affected cellular functions differentially from other family members. Using colon cancer cells expressing wildtype (WT), C-terminus-deleted, or chimeric mutants, diverse cellular functions were explored in 2-dimensional (2D) and 3-dimensional (3D) condition. The C-termini of the proteins were relatively comparable with respect to 2D cell proliferation, although each C-terminal-deletion mutant exhibited increased proliferation relative to the WT. Using chimeric constructs, we found that the TM4SF5 C-terminus was critical for regulating the diverse metastatic functions of TM4SF5, and could positively replace the C-termini of other family members. Replacement of the TM4SF1 or TM4SF4 C-terminus with that of TM4SF5 increased spheroids growth, transwell migration, and invasive dissemination from spheroids in 3D collagen gels. TM4SF5-mediated effects required its extracellular loop 2 linked to the C-terminus via the transmembrane domain 4, with causing c-Src activation. Altogether, the C-terminus of TM4SF5 appears to mediate pro-migratory roles, depending on a structural relay from the second extracellular loop to the C-terminus.

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Human tetraspanin transmembrane 4 superfamily member 4 or intestinal and liver tetraspan membrane protein is overexpressed in hepatocellular carcinoma and accelerates tumor cell growth

Cited by 19 publications

References 23 publications

Genome-wide transcriptome analysis identifies novel gene signatures implicated in human chronic liver disease

Genome-wide transcriptome analysis identifies novel gene signatures implicated in human chronic liver disease

Adenovirus-mediated delivery of siRNA targeting TM4SF4 attenuated liver cancer cell growth <italic>in vitro</italic> and <italic>in vivo</italic>

Differential regulation of cellular functions by the C-termini of transmembrane 4 L six family proteins in 2- or 3-dimensional environment

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Human tetraspanin transmembrane 4 superfamily member 4 or intestinal and liver tetraspan membrane protein is overexpressed in hepatocellular carcinoma and accelerates tumor cell growth

Cited by 19 publications

References 23 publications

Genome-wide transcriptome analysis identifies novel gene signatures implicated in human chronic liver disease

Genome-wide transcriptome analysis identifies novel gene signatures implicated in human chronic liver disease

Adenovirus-mediated delivery of siRNA targeting TM4SF4 attenuated liver cancer cell growth &lt;italic&gt;in vitro&lt;/italic&gt; and &lt;italic&gt;in vivo&lt;/italic&gt;

Differential regulation of cellular functions by the C-termini of transmembrane 4 L six family proteins in 2- or 3-dimensional environment

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Adenovirus-mediated delivery of siRNA targeting TM4SF4 attenuated liver cancer cell growth <italic>in vitro</italic> and <italic>in vivo</italic>