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A Positive TGF-?/c-KIT Feedback Loop Drives Tumor Progression in Advanced Primary Liver Cancer.

ABSTRACT: Hepatocellular carcinoma (HCC) is globally the second most common cause of cancer mortality. The majority of HCC patients are diagnosed at advanced stage disease for which no curative treatments exist. TGF-? has been identified as a potential therapeutic target. However, the molecular mechanisms mediating its functional switch from a tumor suppressor to tumor promoter in HCC and its interactions with other signaling pathways are poorly understood. Here, we demonstrate an aberrant molecular network between the TGF-? and c-KIT pathway that mediates the functional switch of TGF-? to a driver of tumor progression in HCC. TGF-?/SMAD2 signaling transcriptionally regulates expression of the c-KIT receptor ligand (stem cell factor [SCF]) with subsequent auto- and paracrine activation of c-KIT/JAK1/STAT3 signaling. SCF induces TGF-?1 ligand expression via STAT3, thereby forming a positive feedback loop between TGF-?/SMAD and SCF/c-KIT signaling. This network neutralizes TGF-?-mediated cell cycle inhibition and induces tumor cell proliferation, epithelial-to-mesenchymal-transition, migration, and invasion. Disruption of this feedback loop inhibits TGF-? tumor-promoting effects and restores its antiproliferative functions. Consistent with our in vitro data, we demonstrate SCF overexpression and its correlation to SMAD2 and STAT3 activation in human HCC tumors, advanced tumor-node-metastasis stages, and shorter survival.Canonical TGF-? and c-KIT signaling forms a positive, tumor-promoting feedback loop. Disruption of this loop restores TGF-? tumor suppressor function and provides the rationale for targeting the TGF-?/SCF axis as a novel therapeutic strategy for HCC.

SUBMITTER: Rojas A

PROVIDER: S-EPMC4909706 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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A Positive TGF-β/c-KIT Feedback Loop Drives Tumor Progression in Advanced Primary Liver Cancer.

Rojas Andres A Zhang Pingyu P Wang Ying Y Foo Wai Chin WC Muñoz Nina M NM Xiao Lianchun L Wang Jing J Gores Gregory J GJ Hung Mien-Chie MC Blechacz Boris B

Neoplasia (New York, N.Y.) 20160601 6

<h4>Unlabelled</h4>Hepatocellular carcinoma (HCC) is globally the second most common cause of cancer mortality. The majority of HCC patients are diagnosed at advanced stage disease for which no curative treatments exist. TGF-β has been identified as a potential therapeutic target. However, the molecular mechanisms mediating its functional switch from a tumor suppressor to tumor promoter in HCC and its interactions with other signaling pathways are poorly understood. Here, we demonstrate an aberr ...[more]

PMID: 27292026

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Project description:BackgroundThe transforming growth factor-β (TGF-β) signaling pathway plays an essential role in maintaining homeostasis in joints affected by osteoarthritis (OA). However, the specific mechanism of non-SMAD and classical SMAD signaling interactions is still unclear, which needs to be further explored.MethodsIn ATDC5 cells, USP15 overexpression and knockout were performed using the transfected lentivirus USP15 and Crispr/Cas9. Western blotting and immunofluorescence staining were used to test p-SMAD2 and cartilage phenotype-related molecular markers. In rat OA models, immunohistochemistry, hematoxylin and eosin (HE)/Safranin-O fast green staining, and histology were used to examine the regulatory activity of USP15 in TGF-β/SMAD2 signaling and the cartilage phenotype. Then, ERK2 overexpression and knockout were performed. The expressions of USP15, p-SMAD2, and the cartilage phenotype were evaluated in vitro and in vivo. To address whether USP15 is required for ERK2 and TGF-β/SMAD2 signaling, we performed rescue experiments in vitro and in vivo. Immunoprecipitation and deubiquitination assays were used to examine whether USP15 could bind to ERK2 and affect the deubiquitination of ERK2. Finally, whether USP15 regulates the level of p-ERK1/2 was evaluated by western blotting, immunofluorescence staining, and immunohistochemistry in vitro and in vivo.ResultsOur results indicated that USP15 stimulated TGF-β/SMAD2 signaling and the cartilage phenotype. Moreover, ERK2 required USP15 to influence TGF-β/SMAD2 signaling for regulating the cartilage phenotype in vivo and in vitro. And USP15 can form a complex with ERK2 to regulate ubiquitination of ERK2. Interestingly, USP15 did not regulate the stability of ERK2 but increased the level of p-ERK1/2 to further enhance the TGF-β/SMAD2 signaling pathway.ConclusionsTaken together, our study revealed positive feedback regulation between USP15 and ERK2, which played a critical role in TGF-β/SMAD2 signaling to inhibit OA progression. Therefore, this specific mechanism can guide the clinical treatment of OA.

Dataset Information

A Positive TGF-?/c-KIT Feedback Loop Drives Tumor Progression in Advanced Primary Liver Cancer.

Publications

A Positive TGF-β/c-KIT Feedback Loop Drives Tumor Progression in Advanced Primary Liver Cancer.

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