Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma

Cheolhee Won, Byung Hak Kim, Eun Hee Yi, Kyung Ju Choi, Eun Kyung Kim, Jong Min Jeong, Jae Ho Lee, Ja June Jang, Jung Hwan Yoon, Won Il Jeong, In Chul Park, Tae Woo Kim, Sun Sik Bae, Valentina M. Factor, Stephanie Ma, Snorri S. Thorgeirsson, Yun Han Lee, Sang Kyu Ye

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Enhanced expression of the cancer stem cell (CSC) marker, CD133, is closely associated with a higher rate of tumor formation and poor prognosis in hepatocellular carcinoma (HCC) patients. Despite its clinical significance, the molecular mechanism underlying the deregulation of CD133 during tumor progression remains to be clarified. Here, we report on a novel mechanism by which interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling up-regulates expression of CD133 and promotes HCC progression. STAT3 activated by IL-6 rapidly bound to CD133 promoter and increased protein levels of CD133 in HCC cells. Reversely, in hypoxic conditions, RNA interference silencing of STAT3 resulted in decrease of CD133 levels, even in the presence of IL-6, with a concomitant decrease of hypoxia-inducible factor 1 alpha (HIF-1α) expression. Active STAT3 interacted with nuclear factor kappa B (NF-κB) p65 subunit to positively regulate the transcription of HIF-1α providing a mechanistic explanation on how those three oncogenes work together to increase the activity of CD133 in a hypoxic liver microenvironment. Activation of STAT3 and its consequent induction of HIF-1α and CD133 expression were not observed in Toll-like receptor 4/IL-6 double-knockout mice. Long-term silencing of CD133 by a lentiviral-based approach inhibited cancer cell-cycle progression and suppressed in vivo tumorigenicity by down-regulating expression of cytokinesis-related genes, such as TACC1, ACF7, and CKAP5. We also found that sorafenib and STAT3 inhibitor nifuroxazide inhibit HCC xenograft formation by blocking activation of STAT3 and expression of CD133 and HIF-1α proteins. Conclusion: IL-6/STAT3 signaling induces expression of CD133 through functional cooperation with NF-κB and HIF-1α during liver carcinogenesis. Targeting STAT3-mediated CD133 up-regulation may represent a novel, effective treatment by eradicating the liver tumor microenvironment.

Original languageEnglish
Pages (from-to)1160-1173
Number of pages14
JournalHepatology
Volume62
Issue number4
DOIs
Publication statusPublished - 2015 Oct 1

Fingerprint

Hypoxia-Inducible Factor 1
STAT3 Transcription Factor
Hepatocellular Carcinoma
Interleukin-6
Up-Regulation
NF-kappa B
RNA Interference
Liver
Neoplasms
Toll-Like Receptor 4
Tumor Microenvironment
Cytokinesis
Neoplastic Stem Cells
Oncogenes
Heterografts
Knockout Mice
Cell Cycle
Carcinogenesis
Proteins
Genes

ASJC Scopus subject areas

  • Hepatology

Cite this

Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma. / Won, Cheolhee; Kim, Byung Hak; Yi, Eun Hee; Choi, Kyung Ju; Kim, Eun Kyung; Jeong, Jong Min; Lee, Jae Ho; Jang, Ja June; Yoon, Jung Hwan; Jeong, Won Il; Park, In Chul; Kim, Tae Woo; Bae, Sun Sik; Factor, Valentina M.; Ma, Stephanie; Thorgeirsson, Snorri S.; Lee, Yun Han; Ye, Sang Kyu.

In: Hepatology, Vol. 62, No. 4, 01.10.2015, p. 1160-1173.

Research output: Contribution to journalArticle

Won, C, Kim, BH, Yi, EH, Choi, KJ, Kim, EK, Jeong, JM, Lee, JH, Jang, JJ, Yoon, JH, Jeong, WI, Park, IC, Kim, TW, Bae, SS, Factor, VM, Ma, S, Thorgeirsson, SS, Lee, YH & Ye, SK 2015, 'Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma', Hepatology, vol. 62, no. 4, pp. 1160-1173. https://doi.org/10.1002/hep.27968
Won, Cheolhee ; Kim, Byung Hak ; Yi, Eun Hee ; Choi, Kyung Ju ; Kim, Eun Kyung ; Jeong, Jong Min ; Lee, Jae Ho ; Jang, Ja June ; Yoon, Jung Hwan ; Jeong, Won Il ; Park, In Chul ; Kim, Tae Woo ; Bae, Sun Sik ; Factor, Valentina M. ; Ma, Stephanie ; Thorgeirsson, Snorri S. ; Lee, Yun Han ; Ye, Sang Kyu. / Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma. In: Hepatology. 2015 ; Vol. 62, No. 4. pp. 1160-1173.
@article{a8671bf168e746298fd3009761522484,
title = "Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma",
abstract = "Enhanced expression of the cancer stem cell (CSC) marker, CD133, is closely associated with a higher rate of tumor formation and poor prognosis in hepatocellular carcinoma (HCC) patients. Despite its clinical significance, the molecular mechanism underlying the deregulation of CD133 during tumor progression remains to be clarified. Here, we report on a novel mechanism by which interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling up-regulates expression of CD133 and promotes HCC progression. STAT3 activated by IL-6 rapidly bound to CD133 promoter and increased protein levels of CD133 in HCC cells. Reversely, in hypoxic conditions, RNA interference silencing of STAT3 resulted in decrease of CD133 levels, even in the presence of IL-6, with a concomitant decrease of hypoxia-inducible factor 1 alpha (HIF-1α) expression. Active STAT3 interacted with nuclear factor kappa B (NF-κB) p65 subunit to positively regulate the transcription of HIF-1α providing a mechanistic explanation on how those three oncogenes work together to increase the activity of CD133 in a hypoxic liver microenvironment. Activation of STAT3 and its consequent induction of HIF-1α and CD133 expression were not observed in Toll-like receptor 4/IL-6 double-knockout mice. Long-term silencing of CD133 by a lentiviral-based approach inhibited cancer cell-cycle progression and suppressed in vivo tumorigenicity by down-regulating expression of cytokinesis-related genes, such as TACC1, ACF7, and CKAP5. We also found that sorafenib and STAT3 inhibitor nifuroxazide inhibit HCC xenograft formation by blocking activation of STAT3 and expression of CD133 and HIF-1α proteins. Conclusion: IL-6/STAT3 signaling induces expression of CD133 through functional cooperation with NF-κB and HIF-1α during liver carcinogenesis. Targeting STAT3-mediated CD133 up-regulation may represent a novel, effective treatment by eradicating the liver tumor microenvironment.",
author = "Cheolhee Won and Kim, {Byung Hak} and Yi, {Eun Hee} and Choi, {Kyung Ju} and Kim, {Eun Kyung} and Jeong, {Jong Min} and Lee, {Jae Ho} and Jang, {Ja June} and Yoon, {Jung Hwan} and Jeong, {Won Il} and Park, {In Chul} and Kim, {Tae Woo} and Bae, {Sun Sik} and Factor, {Valentina M.} and Stephanie Ma and Thorgeirsson, {Snorri S.} and Lee, {Yun Han} and Ye, {Sang Kyu}",
year = "2015",
month = "10",
day = "1",
doi = "10.1002/hep.27968",
language = "English",
volume = "62",
pages = "1160--1173",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "4",

}

TY - JOUR

T1 - Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma

AU - Won, Cheolhee

AU - Kim, Byung Hak

AU - Yi, Eun Hee

AU - Choi, Kyung Ju

AU - Kim, Eun Kyung

AU - Jeong, Jong Min

AU - Lee, Jae Ho

AU - Jang, Ja June

AU - Yoon, Jung Hwan

AU - Jeong, Won Il

AU - Park, In Chul

AU - Kim, Tae Woo

AU - Bae, Sun Sik

AU - Factor, Valentina M.

AU - Ma, Stephanie

AU - Thorgeirsson, Snorri S.

AU - Lee, Yun Han

AU - Ye, Sang Kyu

PY - 2015/10/1

Y1 - 2015/10/1

N2 - Enhanced expression of the cancer stem cell (CSC) marker, CD133, is closely associated with a higher rate of tumor formation and poor prognosis in hepatocellular carcinoma (HCC) patients. Despite its clinical significance, the molecular mechanism underlying the deregulation of CD133 during tumor progression remains to be clarified. Here, we report on a novel mechanism by which interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling up-regulates expression of CD133 and promotes HCC progression. STAT3 activated by IL-6 rapidly bound to CD133 promoter and increased protein levels of CD133 in HCC cells. Reversely, in hypoxic conditions, RNA interference silencing of STAT3 resulted in decrease of CD133 levels, even in the presence of IL-6, with a concomitant decrease of hypoxia-inducible factor 1 alpha (HIF-1α) expression. Active STAT3 interacted with nuclear factor kappa B (NF-κB) p65 subunit to positively regulate the transcription of HIF-1α providing a mechanistic explanation on how those three oncogenes work together to increase the activity of CD133 in a hypoxic liver microenvironment. Activation of STAT3 and its consequent induction of HIF-1α and CD133 expression were not observed in Toll-like receptor 4/IL-6 double-knockout mice. Long-term silencing of CD133 by a lentiviral-based approach inhibited cancer cell-cycle progression and suppressed in vivo tumorigenicity by down-regulating expression of cytokinesis-related genes, such as TACC1, ACF7, and CKAP5. We also found that sorafenib and STAT3 inhibitor nifuroxazide inhibit HCC xenograft formation by blocking activation of STAT3 and expression of CD133 and HIF-1α proteins. Conclusion: IL-6/STAT3 signaling induces expression of CD133 through functional cooperation with NF-κB and HIF-1α during liver carcinogenesis. Targeting STAT3-mediated CD133 up-regulation may represent a novel, effective treatment by eradicating the liver tumor microenvironment.

AB - Enhanced expression of the cancer stem cell (CSC) marker, CD133, is closely associated with a higher rate of tumor formation and poor prognosis in hepatocellular carcinoma (HCC) patients. Despite its clinical significance, the molecular mechanism underlying the deregulation of CD133 during tumor progression remains to be clarified. Here, we report on a novel mechanism by which interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling up-regulates expression of CD133 and promotes HCC progression. STAT3 activated by IL-6 rapidly bound to CD133 promoter and increased protein levels of CD133 in HCC cells. Reversely, in hypoxic conditions, RNA interference silencing of STAT3 resulted in decrease of CD133 levels, even in the presence of IL-6, with a concomitant decrease of hypoxia-inducible factor 1 alpha (HIF-1α) expression. Active STAT3 interacted with nuclear factor kappa B (NF-κB) p65 subunit to positively regulate the transcription of HIF-1α providing a mechanistic explanation on how those three oncogenes work together to increase the activity of CD133 in a hypoxic liver microenvironment. Activation of STAT3 and its consequent induction of HIF-1α and CD133 expression were not observed in Toll-like receptor 4/IL-6 double-knockout mice. Long-term silencing of CD133 by a lentiviral-based approach inhibited cancer cell-cycle progression and suppressed in vivo tumorigenicity by down-regulating expression of cytokinesis-related genes, such as TACC1, ACF7, and CKAP5. We also found that sorafenib and STAT3 inhibitor nifuroxazide inhibit HCC xenograft formation by blocking activation of STAT3 and expression of CD133 and HIF-1α proteins. Conclusion: IL-6/STAT3 signaling induces expression of CD133 through functional cooperation with NF-κB and HIF-1α during liver carcinogenesis. Targeting STAT3-mediated CD133 up-regulation may represent a novel, effective treatment by eradicating the liver tumor microenvironment.

UR - http://www.scopus.com/inward/record.url?scp=84942551966&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84942551966&partnerID=8YFLogxK

U2 - 10.1002/hep.27968

DO - 10.1002/hep.27968

M3 - Article

VL - 62

SP - 1160

EP - 1173

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 4

ER -