Tetraspan TM4SF5-dependent direct activation of FAK and metastatic potential of hepatocarcinoma cells

Jung, Oisun; Choi, Sungyeol; Jang, Sun-Bok; Lee, Sin-Ae; Lim, Ssang‐Taek; Choi, Yun‐Shik; Kim, Hye-Jin; Kim, Do-Hee; Kwak, Tae Kyoung; Kim, Hyeonjung; Kang, Min‐Kyung; Lee, Mi-Sook; Park, Sook Young; Ryu, Jihye; Jeong, Doyoung; Cheong, Hae‐Kap; Kim, Jong Hun; Park, Ki Hun; Lee, Bong-Jin; Schlaepfer, David D.; Lee, Sang Eun

doi:10.1242/jcs.100586

Cited by 45 publications

(65 citation statements)

References 41 publications

(60 reference statements)

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“…Interestingly, the IL-6-independent STAT3 activity appeared to be negatively correlated with FAK activity in the SNU761-TM4SF5 cells. FAK is also hyperactivated in TM4SF5-positive liver cancer cells (10,20). Therefore, FAK downstream of TM4SF5 might compete with IL-6-independent STAT3 activity; however, FAK did not affect IL-6-dependent STAT3 activity.…”

Section: Discussionmentioning

confidence: 97%

“…TM4SF5 collaborates with integrins and regulates cell migration and invasion (28). In addition, the cytosolic region of TM4SF5 interacts with and activates FAK and c-Src, promoting directional migration and invasive protrusions (10,29). Therefore, TM4SF5-mediated FAK activation can be critical during tumor progression (8).…”

Section: Discussionmentioning

confidence: 99%

“…EGF/EGFR activates STAT3, but it does not lead to mitogenic effects (33), and fibronectin-initiated adhesion activates STAT3, leading to epithelial-mesenchymal transition (EMT) by EGFR-dependent and -independent mechanisms (34). Interestingly, both FAK and EGFR can associate with TM4SF5 (10,35). TM4SF5-mediated c-Src activity (29) also may be a candidate for causing STAT3 overactivation, as c-Src is upstream of STAT3 (36).…”

Section: Discussionmentioning

confidence: 99%

“…We next wondered whether FAK affected STAT3 phosphorylation. To test this, we used the specific FAK inhibitor PF271 (10). FAK inhibition in Chang cells did not alter pY 705 STAT3 or its translocation into the nucleus under any circumstances, although FAK activity and FA formation were decreased (Fig.…”

Section: Stat3 Suppression Inhibited Il-6-mediated Fa Formation By Chmentioning

confidence: 99%

“…TM4SF5 is overexpressed in a diverse set of cancers, and its overexpression in hepatocytes enhances their tumorigenic proliferation, migration, and invasion (8). TM4SF5 binds and activates FAK, thereby directing motility, and this interaction can be the basis for adhesion-dependent FAK activation by TM4SF5 (10). Therefore, TM4SF5 causes abnormal cell growth and enhances the metastatic potential of liver cancer cells (8,9).…”

mentioning

confidence: 99%

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Cross Talk between the TM4SF5/Focal Adhesion Kinase and the Interleukin-6/STAT3 Pathways Promotes Immune Escape of Human Liver Cancer Cells

Ryu

Kang

Lee

et al. 2014

Molecular and Cellular Biology

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TM4SF5 overexpressed in hepatocellular carcinoma activates focal adhesion kinase (FAK) during tumor cell migration. However, it remains unknown how TM4SF5 in hepatocellular carcinoma cells compromises with immune actions initiated by extracellular cytokines. Normal and cancerous hepatocytes with or without TM4SF5 expression were analyzed for the effects of cytokine signaling activity on TM4SF5/FAK signaling and metastatic potential. We found that interleukin-6 (IL-6) was differentially expressed in hepatocytes depending on cancerous malignancy and TM4SF5 expression. IL-6 treatment activated FAK and STAT3 and enhanced focal adhesion (FA) formation in TM4SF5-null cells, but it decreased TM4SF5-dependent FAK activity and FA formation in SNU761-TM4SF5 cells. STAT3 suppression abolished the IL-6-mediated effects in normal Chang cells, but it did not recover the TM4SF5-dependent FAK activity that was inhibited by IL-6 treatment in cancerous SNU761-TM4SF5 cells. In addition, modulation of FAK activity did not change the IL-6-mediated STAT3 activity in either the Chang or SNU761 cell system. TM4SF5 expression in SNU761 cells caused invasive extracellular matrix degradation negatively depending on IL-6/IL-6 receptor (IL-6R) signaling. Thus, it is likely that hepatic cancer cells adopt TM4SF5-dependent FAK activation and metastatic potential by lowering IL-6 expression and avoiding its immunological action through the IL-6-STAT3 pathway.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Stat3 Suppression Inhibited Il-6-mediated Fa Formation By Chmentioning

confidence: 99%

mentioning

confidence: 99%

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Cross Talk between the TM4SF5/Focal Adhesion Kinase and the Interleukin-6/STAT3 Pathways Promotes Immune Escape of Human Liver Cancer Cells

Ryu

Kang

Lee

et al. 2014

Molecular and Cellular Biology

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Interaction of tetraspan(in) TM4SF5 with CD44 promotes self‐renewal and circulating capacities of hepatocarcinoma cells

Lee

Ryu

et al. 2015

Hepatology

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Tumor metastasis involves circulating and tumor-initiating capacities of metastatic cancer cells. Epithelial-mesenchymal transition (EMT) is related to self-renewal capacity and circulating tumor cell (CTC) characteristics for tumor metastasis. Although tumor metastasis is a life-threatening, complicated process that occurs through circulation of tumor cells, mechanistic aspects of self-renewal and circulating capacities have been largely unknown. Hepatic transmembrane 4 L six family member 5 (TM4SF5) promotes EMT for malignant growth and migration, so it was rationalized that TM4SF5, as a hepatocellular carcinoma (HCC) biomarker, might be important for metastatic potential. Here, self-renewal capacity by TM4SF5 was mechanistically explored using hepatocarcinoma cells with or without TM4SF5 expression, and we explored whether they became CTCs using mouse liverorthotopic model systems. We found that TM4SF5-dependent sphere growth correlated with CD242 , aldehyde dehydrogenase (ALDH) activity, as well as a physical association between CD44 and TM4SF5. Interaction between TM4SF5 and CD44 was through their extracellular domains with N-glycosylation modifications. TM4SF5/CD44 interaction activated proto-oncogene tyrosine-protein kinase Src (c-Src)/signal transducer and activator of transcription 3 (STAT3)/Twist-related protein 1 (Twist1)/B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) signaling for spheroid formation, whereas disturbing the interaction, expression, or activity of any component in this signaling pathway inhibited spheroid formation. In serial xenografts using 2005,000 cells per injection, TM4SF5-positive tumors exhibited subpopulations with locally increased CD44 expressions, supporting for tumor cell differentiation. TM4SF5-positive, but not TM4SF5-or CD44-knocked-down, cells were identified circulating in blood 4-6 weeks after orthotopic liver injection using in vivo laser scanning endomicroscopy. Anti-TM4SF5 reagent blocked their metastasis to distal intestinal organs. Conclusion: TM4SF5 promotes self-renewal and CTC properties supported by TM4SF5 1 /CD442 markers during HCC metastasis. (HEPATOLOGY 2015;61:1978-1997 H epatocellular carcinoma (HCC) is the thirdmost common cause of mortality resulting from cancer.1 Although hepatic resection and liver transplantation represent first-line treatments for HCC, 2 the second-line treatment for HCC patients in advanced stages has shown limited efficacy.3 Moreover, metastatic recurrence renders this carcinoma resistant to any significant chemopreventive effects.

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Liver‐originated small extracellular vesicles with TM4SF5 target brown adipose tissue for homeostatic glucose clearance

Jung

Kim

et al. 2022

J of Extracellular Vesicle

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Transmembrane 4 L six family member 5 (TM4SF5) is involved in chronic liver disease, although its role in glucose homeostasis remains unknown. TM4SF5 deficiency caused age-dependent glucose (in)tolerance with no link to insulin sensitivity. Further, hepatic TM4SF5 binding to GLUT1 promoted glucose uptake and glycolysis. Excessive glucose repletion caused hepatocytes to secrete small extracellular vesicles (sEVs) loaded with TM4SF5 (hep-sEV Tm4sf5 ), suggesting a role for sEV Tm4sf5 in glucose metabolism and homeostasis. Hep-sEV Tm4sf5 were smaller than sEV Control and recruit proteins for efficient organ tropism. Liver-derived sEVs, via a liver-closed vein circuit (LCVC) using hepatic TM4SF5-overexpressing (Alb-Tm4sf5 TG) mice (liv-sEV Tm4sf5 ), improved glucose tolerance in Tmsf −/− KO mice and targeted brown adipose tissues (BATs), possibly allowing the clearance of blood glucose as heat independent of UCP1. Taken together, hep-sEV Tm4sf5 might clear high extracellular glucose levels more efficiently by targeting BAT compared with hep-sEV Control , suggesting an insulin-like role for sEV™ 4SF5 in affecting age-related metabolic status and thus body weight (BW).

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Tetraspan TM4SF5-dependent direct activation of FAK and metastatic potential of hepatocarcinoma cells

Cited by 45 publications

References 41 publications

Cross Talk between the TM4SF5/Focal Adhesion Kinase and the Interleukin-6/STAT3 Pathways Promotes Immune Escape of Human Liver Cancer Cells

Cross Talk between the TM4SF5/Focal Adhesion Kinase and the Interleukin-6/STAT3 Pathways Promotes Immune Escape of Human Liver Cancer Cells

Interaction of tetraspan(in) TM4SF5 with CD44 promotes self‐renewal and circulating capacities of hepatocarcinoma cells

Liver‐originated small extracellular vesicles with TM4SF5 target brown adipose tissue for homeostatic glucose clearance

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