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

Doohyung Lee, Juri Na, Jihye Ryu, Hye Jin Kim, Seo Hee Nam, Minkyung Kang, Jae Woo Jung, Mi Sook Lee, Haeng Eun Song, Jungeun Choi, Gyu Ho Lee, Tai Young Kim, June Key Chung, Ki Hun Park, Sung Hak Kim, Hyunggee Kim, Howon Seo, Pilhan Kim, Hyewon Youn, Jung Weon Lee

Research output: Contribution to journalArticle

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Abstract

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 liver-orthotopic model systems. We found that TM4SF5-dependent sphere growth correlated with CD24<sup>-</sup>, 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 200~5,000 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<sup>+</sup>/CD44<sup>+(TM4SF5-bound)</sup>/ALDH<sup>+</sup>/CD24<sup>-</sup> markers during HCC metastasis.

Original languageEnglish
Pages (from-to)1978-1997
Number of pages20
JournalHepatology
Volume61
Issue number6
DOIs
Publication statusPublished - 2015 Jun 1

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Neoplasm Metastasis
Neoplasms
Circulating Neoplastic Cells
Aldehyde Dehydrogenase
Epithelial-Mesenchymal Transition
Proto-Oncogene Proteins
Twist-Related Protein 1
Hepatocellular Carcinoma
Liver
Virus Integration
Moloney murine leukemia virus
STAT3 Transcription Factor
Injections
Growth
Glycosylation
Heterografts
Protein-Tyrosine Kinases
Cell Differentiation
Lasers
B-Lymphocytes

ASJC Scopus subject areas

  • Hepatology

Cite this

Interaction of tetraspan(in) TM4SF5 with CD44 promotes self-renewal and circulating capacities of hepatocarcinoma cells. / Lee, Doohyung; Na, Juri; Ryu, Jihye; Kim, Hye Jin; Nam, Seo Hee; Kang, Minkyung; Jung, Jae Woo; Lee, Mi Sook; Song, Haeng Eun; Choi, Jungeun; Lee, Gyu Ho; Kim, Tai Young; Chung, June Key; Park, Ki Hun; Kim, Sung Hak; Kim, Hyunggee; Seo, Howon; Kim, Pilhan; Youn, Hyewon; Lee, Jung Weon.

In: Hepatology, Vol. 61, No. 6, 01.06.2015, p. 1978-1997.

Research output: Contribution to journalArticle

Lee, D, Na, J, Ryu, J, Kim, HJ, Nam, SH, Kang, M, Jung, JW, Lee, MS, Song, HE, Choi, J, Lee, GH, Kim, TY, Chung, JK, Park, KH, Kim, SH, Kim, H, Seo, H, Kim, P, Youn, H & Lee, JW 2015, 'Interaction of tetraspan(in) TM4SF5 with CD44 promotes self-renewal and circulating capacities of hepatocarcinoma cells', Hepatology, vol. 61, no. 6, pp. 1978-1997. https://doi.org/10.1002/hep.27721
Lee, Doohyung ; Na, Juri ; Ryu, Jihye ; Kim, Hye Jin ; Nam, Seo Hee ; Kang, Minkyung ; Jung, Jae Woo ; Lee, Mi Sook ; Song, Haeng Eun ; Choi, Jungeun ; Lee, Gyu Ho ; Kim, Tai Young ; Chung, June Key ; Park, Ki Hun ; Kim, Sung Hak ; Kim, Hyunggee ; Seo, Howon ; Kim, Pilhan ; Youn, Hyewon ; Lee, Jung Weon. / Interaction of tetraspan(in) TM4SF5 with CD44 promotes self-renewal and circulating capacities of hepatocarcinoma cells. In: Hepatology. 2015 ; Vol. 61, No. 6. pp. 1978-1997.
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abstract = "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 liver-orthotopic model systems. We found that TM4SF5-dependent sphere growth correlated with CD24-, 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 200~5,000 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+/CD44+(TM4SF5-bound)/ALDH+/CD24- markers during HCC metastasis.",
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T1 - Interaction of tetraspan(in) TM4SF5 with CD44 promotes self-renewal and circulating capacities of hepatocarcinoma cells

AU - Lee, Doohyung

AU - Na, Juri

AU - Ryu, Jihye

AU - Kim, Hye Jin

AU - Nam, Seo Hee

AU - Kang, Minkyung

AU - Jung, Jae Woo

AU - Lee, Mi Sook

AU - Song, Haeng Eun

AU - Choi, Jungeun

AU - Lee, Gyu Ho

AU - Kim, Tai Young

AU - Chung, June Key

AU - Park, Ki Hun

AU - Kim, Sung Hak

AU - Kim, Hyunggee

AU - Seo, Howon

AU - Kim, Pilhan

AU - Youn, Hyewon

AU - Lee, Jung Weon

PY - 2015/6/1

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N2 - 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 liver-orthotopic model systems. We found that TM4SF5-dependent sphere growth correlated with CD24-, 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 200~5,000 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+/CD44+(TM4SF5-bound)/ALDH+/CD24- markers during HCC metastasis.

AB - 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 liver-orthotopic model systems. We found that TM4SF5-dependent sphere growth correlated with CD24-, 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 200~5,000 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+/CD44+(TM4SF5-bound)/ALDH+/CD24- markers during HCC metastasis.

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