IL6-mediated inflammatory loop reprograms normal to epithelial-mesenchymal transition+ metastatic cancer stem cells in preneoplastic liver of transforming growth factor beta–deficient β2-spectrin+/− mice

Abhisek Mitra; Jun Yan; Xueqing Xia; Shouhao Zhou; Jian Chen; Lopa Mishra; Shulin Li

doi:10.1002/hep.28951

IL6-mediated inflammatory loop reprograms normal to epithelial-mesenchymal transition⁺ metastatic cancer stem cells in preneoplastic liver of transforming growth factor beta–deficient β2-spectrin^+/− mice

Abhisek Mitra, Jun Yan, Xueqing Xia, Shouhao Zhou, Jian Chen, Lopa Mishra, Shulin Li

Research output: Contribution to journal › Article › peer-review

52 Scopus citations

Abstract

Hepatocellular carcinoma (HCC) is the second-leading cause of cancer-related deaths worldwide with a poor survival rate. As many as 40% of HCCs are clonal, with alteration of key tumor-suppressor pathways in stem cells as the primary cause of HCC initiation. However, mechanisms that generate metastatic stem cells in preneoplastic liver tissue are not well understood. We hypothesized that chronic inflammation is a major driver of the transformation of genetically defective liver stem cells (LSCs) into highly metastatic liver cancer cells in premalignant liver tissue. We developed models of chronic inflammation in wild-type (WT) and β2-spectrin (β2SP)^+/− (SPTBN1) mice. CD133⁺ LSCs derived from preneoplastic livers of β2SP^+/− mice treated with interleukin-6 (pIL6; ^IL6β2SP^+/− LSCs) were highly tumorigenic and metastatic, whereas those derived from WT mice treated with pIL6 (^IL6WT LSCs) had significantly less proliferation and no tumorigenic properties. ^IL6β2SP^+/− LSCs not only exhibited nuclear localization of Twist and Slug, markers of epithelial-mesenchymal transition (EMT), but also constitutive activation of nuclear factor kappa B (NFκB; RELA). Knockdown of NFκB decreased the EMT phenotypes and metastatic capacity of these cells. NFκB in ^IL6β2SP^+/− LSCs was activated by transforming growth factor β (TGFβ)-activated kinase 1 (TAK1; MAP3K7), which is associated with poor survival in HCC and interleukin-6 (IL6) expression. The amount of constitutively activated NFκB increased dramatically from normal to cirrhotic to HCC tissues from human patients. Conclusion: IL6-mediated inflammation programs constitutive activation of the TAK1-NFκB signaling cascade in CD133⁺ LSCs, and this program interacts with deficient TGFβ signaling, thereby accelerating the transformation of normal LSCs to metastatic cancer stem cells (mCSCs). Indeed, this study delineates the development of EMT-positive mCSCs in HCC-free liver tissue upon chronic inflammation. (Hepatology 2017;65:1222-1236).

Original language	English (US)
Pages (from-to)	1222-1236
Number of pages	15
Journal	Hepatology
Volume	65
Issue number	4
DOIs	https://doi.org/10.1002/hep.28951
State	Published - Apr 1 2017

ASJC Scopus subject areas

Hepatology

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IL6-mediated inflammatory loop reprograms normal to epithelial-mesenchymal transition⁺ metastatic cancer stem cells in preneoplastic liver of transforming growth factor beta–deficient β2-spectrin^+/− mice. / Mitra, Abhisek; Yan, Jun; Xia, Xueqing et al.
In: Hepatology, Vol. 65, No. 4, 01.04.2017, p. 1222-1236.

Research output: Contribution to journal › Article › peer-review

@article{6d15da15a4454d03b74e56569a9c99a7,

title = "IL6-mediated inflammatory loop reprograms normal to epithelial-mesenchymal transition+ metastatic cancer stem cells in preneoplastic liver of transforming growth factor beta–deficient β2-spectrin+/− mice",

abstract = "Hepatocellular carcinoma (HCC) is the second-leading cause of cancer-related deaths worldwide with a poor survival rate. As many as 40% of HCCs are clonal, with alteration of key tumor-suppressor pathways in stem cells as the primary cause of HCC initiation. However, mechanisms that generate metastatic stem cells in preneoplastic liver tissue are not well understood. We hypothesized that chronic inflammation is a major driver of the transformation of genetically defective liver stem cells (LSCs) into highly metastatic liver cancer cells in premalignant liver tissue. We developed models of chronic inflammation in wild-type (WT) and β2-spectrin (β2SP)+/− (SPTBN1) mice. CD133+ LSCs derived from preneoplastic livers of β2SP+/− mice treated with interleukin-6 (pIL6; IL6β2SP+/− LSCs) were highly tumorigenic and metastatic, whereas those derived from WT mice treated with pIL6 (IL6WT LSCs) had significantly less proliferation and no tumorigenic properties. IL6β2SP+/− LSCs not only exhibited nuclear localization of Twist and Slug, markers of epithelial-mesenchymal transition (EMT), but also constitutive activation of nuclear factor kappa B (NFκB; RELA). Knockdown of NFκB decreased the EMT phenotypes and metastatic capacity of these cells. NFκB in IL6β2SP+/− LSCs was activated by transforming growth factor β (TGFβ)-activated kinase 1 (TAK1; MAP3K7), which is associated with poor survival in HCC and interleukin-6 (IL6) expression. The amount of constitutively activated NFκB increased dramatically from normal to cirrhotic to HCC tissues from human patients. Conclusion: IL6-mediated inflammation programs constitutive activation of the TAK1-NFκB signaling cascade in CD133+ LSCs, and this program interacts with deficient TGFβ signaling, thereby accelerating the transformation of normal LSCs to metastatic cancer stem cells (mCSCs). Indeed, this study delineates the development of EMT-positive mCSCs in HCC-free liver tissue upon chronic inflammation. (Hepatology 2017;65:1222-1236).",

author = "Abhisek Mitra and Jun Yan and Xueqing Xia and Shouhao Zhou and Jian Chen and Lopa Mishra and Shulin Li",

note = "Publisher Copyright: {\textcopyright} 2016 by the American Association for the Study of Liver Diseases.",

year = "2017",

month = apr,

day = "1",

doi = "10.1002/hep.28951",

language = "English (US)",

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T1 - IL6-mediated inflammatory loop reprograms normal to epithelial-mesenchymal transition+ metastatic cancer stem cells in preneoplastic liver of transforming growth factor beta–deficient β2-spectrin+/− mice

AU - Mitra, Abhisek

AU - Yan, Jun

AU - Xia, Xueqing

AU - Zhou, Shouhao

AU - Chen, Jian

AU - Mishra, Lopa

AU - Li, Shulin

PY - 2017/4/1

Y1 - 2017/4/1

N2 - Hepatocellular carcinoma (HCC) is the second-leading cause of cancer-related deaths worldwide with a poor survival rate. As many as 40% of HCCs are clonal, with alteration of key tumor-suppressor pathways in stem cells as the primary cause of HCC initiation. However, mechanisms that generate metastatic stem cells in preneoplastic liver tissue are not well understood. We hypothesized that chronic inflammation is a major driver of the transformation of genetically defective liver stem cells (LSCs) into highly metastatic liver cancer cells in premalignant liver tissue. We developed models of chronic inflammation in wild-type (WT) and β2-spectrin (β2SP)+/− (SPTBN1) mice. CD133+ LSCs derived from preneoplastic livers of β2SP+/− mice treated with interleukin-6 (pIL6; IL6β2SP+/− LSCs) were highly tumorigenic and metastatic, whereas those derived from WT mice treated with pIL6 (IL6WT LSCs) had significantly less proliferation and no tumorigenic properties. IL6β2SP+/− LSCs not only exhibited nuclear localization of Twist and Slug, markers of epithelial-mesenchymal transition (EMT), but also constitutive activation of nuclear factor kappa B (NFκB; RELA). Knockdown of NFκB decreased the EMT phenotypes and metastatic capacity of these cells. NFκB in IL6β2SP+/− LSCs was activated by transforming growth factor β (TGFβ)-activated kinase 1 (TAK1; MAP3K7), which is associated with poor survival in HCC and interleukin-6 (IL6) expression. The amount of constitutively activated NFκB increased dramatically from normal to cirrhotic to HCC tissues from human patients. Conclusion: IL6-mediated inflammation programs constitutive activation of the TAK1-NFκB signaling cascade in CD133+ LSCs, and this program interacts with deficient TGFβ signaling, thereby accelerating the transformation of normal LSCs to metastatic cancer stem cells (mCSCs). Indeed, this study delineates the development of EMT-positive mCSCs in HCC-free liver tissue upon chronic inflammation. (Hepatology 2017;65:1222-1236).

AB - Hepatocellular carcinoma (HCC) is the second-leading cause of cancer-related deaths worldwide with a poor survival rate. As many as 40% of HCCs are clonal, with alteration of key tumor-suppressor pathways in stem cells as the primary cause of HCC initiation. However, mechanisms that generate metastatic stem cells in preneoplastic liver tissue are not well understood. We hypothesized that chronic inflammation is a major driver of the transformation of genetically defective liver stem cells (LSCs) into highly metastatic liver cancer cells in premalignant liver tissue. We developed models of chronic inflammation in wild-type (WT) and β2-spectrin (β2SP)+/− (SPTBN1) mice. CD133+ LSCs derived from preneoplastic livers of β2SP+/− mice treated with interleukin-6 (pIL6; IL6β2SP+/− LSCs) were highly tumorigenic and metastatic, whereas those derived from WT mice treated with pIL6 (IL6WT LSCs) had significantly less proliferation and no tumorigenic properties. IL6β2SP+/− LSCs not only exhibited nuclear localization of Twist and Slug, markers of epithelial-mesenchymal transition (EMT), but also constitutive activation of nuclear factor kappa B (NFκB; RELA). Knockdown of NFκB decreased the EMT phenotypes and metastatic capacity of these cells. NFκB in IL6β2SP+/− LSCs was activated by transforming growth factor β (TGFβ)-activated kinase 1 (TAK1; MAP3K7), which is associated with poor survival in HCC and interleukin-6 (IL6) expression. The amount of constitutively activated NFκB increased dramatically from normal to cirrhotic to HCC tissues from human patients. Conclusion: IL6-mediated inflammation programs constitutive activation of the TAK1-NFκB signaling cascade in CD133+ LSCs, and this program interacts with deficient TGFβ signaling, thereby accelerating the transformation of normal LSCs to metastatic cancer stem cells (mCSCs). Indeed, this study delineates the development of EMT-positive mCSCs in HCC-free liver tissue upon chronic inflammation. (Hepatology 2017;65:1222-1236).

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