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?2 spectrin-mediated differentiation repressed the properties of liver cancer stem cells through ?-catenin.

ABSTRACT: ?II-Spectrin (?2SP), a Smad3/4 adaptor protein during transforming growth factor (TGF) ?/Smad signal pathway, plays a critical role in suppressing hepatocarcinogenesis. Dedifferentiation is a distinctive feature of cancer progression. Therefore, we investigated whether the disruption of ?2SP contributed to tumorigenesis of hepatocellular carcinoma (HCC) through the dedifferentiation. Down-regulation of ?2SP in hepatocytes was observed in cirrhotic liver and HCC. The level of ?2SP expression was closely associated with the differentiation status of hepatocytes in rat model of hepatocarcinogenesis and clinical specimens. Transgenic expression of ?2SP in HCC cells promoted the differentiation of HCC cells and suppressed the growth of HCC cells in vitro. Efficient transduction of ?2SP into liver CSCs resulted in a reduction in colony formation ability, spheroid formation capacity, invasive activity, chemo-resistance properties, tumorigenicity in vivo. In addition, ?2 spectrin exerted its effect through ? catenin in liver CSCs. In conclusion, ?2 spectrin repressed the properties of liver CSCs through inducing differentiation; thus, strategies to restore its levels and activities would be a novel strategy for HCC prevention and differentiation therapy.

SUBMITTER: Chen Y

PROVIDER: S-EPMC5859291 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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β2 spectrin-mediated differentiation repressed the properties of liver cancer stem cells through β-catenin.

Chen Yuhua Y Meng Lingling L Shang Haitao H Dou Qian Q Lu Zhiwen Z Liu Liping L Wang Zhijun Z He Xingxing X Song Yuhu Y Song Yuhu Y

Cell death & disease 20180401 4

βII-Spectrin (β2SP), a Smad3/4 adaptor protein during transforming growth factor (TGF) β/Smad signal pathway, plays a critical role in suppressing hepatocarcinogenesis. Dedifferentiation is a distinctive feature of cancer progression. Therefore, we investigated whether the disruption of β2SP contributed to tumorigenesis of hepatocellular carcinoma (HCC) through the dedifferentiation. Down-regulation of β2SP in hepatocytes was observed in cirrhotic liver and HCC. The level of β2SP expression was ...[more]

PMID: 29555987

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Project description: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; IL6 β2SP+/- LSCs) were highly tumorigenic and metastatic, whereas those derived from WT mice treated with pIL6 (IL6 WT LSCs) had significantly less proliferation and no tumorigenic properties. IL6 β2SP+/- 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 IL6 β2SP+/- 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.ConclusionIL6-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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?2 spectrin-mediated differentiation repressed the properties of liver cancer stem cells through ?-catenin.

Publications

β2 spectrin-mediated differentiation repressed the properties of liver cancer stem cells through β-catenin.

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