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Gadd45? silencing impaired viability and metastatic phenotypes in cholangiocarcinoma cells by modulating the EMT pathway.

ABSTRACT: Growth arrest and DNA damage-inducible-? (Gadd45?) is a stress-response protein involved in a number of processes, including cell cycle control, DNA repair, survival and death control, and stress signaling, depending on its interactions. Gadd45? expression is dysregulated in numerous types of cancer, functioning as either a tumor promoter or a tumor suppressor. However, the functions of Gadd45? in cholangiocarcinoma (CCA), particularly in metastasis, has not been studied. The immunohistochemical analysis of Gadd45? expression revealed that 75% of histological specimens from patients with CCA expressed high levels of Gadd45?, and that high Gadd45? expression was associated with metastasis. The role of Gadd45? in CCA was examined using siRNA-mediated gene knockdown in HuCCA-1, a human CCA cell line established from a Thai patient. The effects of Gadd45? downregulation upon cell viability and death, invasion, migration, matrix metalloproteinase (MMP) activity and epithelial-mesenchymal transition (EMT) marker expression were investigated. Gadd45? knockdown impaired cell viability, which was associated with the induction of apoptosis. In addition, there was a marked reduction in invasion and migration, although MMP activity was unaffected. Impairment of these metastatic properties was accompanied by the decreased expression of EMT markers, including Slug, vimentin, claudin-1 and zona occludens protein 1, whereas E-cadherin expression was increased. The present study suggests that Gadd45? is involved in regulating the viability and the metastatic potential of CCA cells, which may be mediated by the modulation of the EMT pathway.

SUBMITTER: Myint KZ

PROVIDER: S-EPMC5778851 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Gadd45β silencing impaired viability and metastatic phenotypes in cholangiocarcinoma cells by modulating the EMT pathway.

Myint Kyaw Zwar KZ Kongpracha Pornparn P Rattanasinganchan Panthip P Leelawat Kawin K Moolthiya Penpak P Chaiyabutr Kittipong K Tohtong Rutaiwan R

Oncology letters 20171228 3

Growth arrest and DNA damage-inducible-β (Gadd45β) is a stress-response protein involved in a number of processes, including cell cycle control, DNA repair, survival and death control, and stress signaling, depending on its interactions. Gadd45β expression is dysregulated in numerous types of cancer, functioning as either a tumor promoter or a tumor suppressor. However, the functions of Gadd45β in cholangiocarcinoma (CCA), particularly in metastasis, has not been studied. The immunohistochemical ...[more]

PMID: 29435034

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Project description:BACKGROUND:Cholangiocarcinoma (CCA), consisting of intrahepatic (IHCCA), perihilar (PHCCA), and distal (DCCA) CCA, is a type of highly aggressive malignancy with a very dismal prognosis. Potential biomarkers and drug targets of CCA are urgently needed. As a new member of the Annexin (ANXA) family, the role of ANXA10 in the progression and prognosis of CCA is unknown. METHODS:Potential PHCCA biomarkers were screened by transcriptome sequencing of 5 pairs of PHCCA and adjacent tissues. The clinical significance of ANXA10 was evaluated by analyzing its correlation with clinicopathological variables, and the prognostic value of ANXA10 was evaluated with univariate and multivariate analyses. The function of ANXA10 in the epithelial-mesenchymal transition (EMT), proliferation, invasion and metastasis was detected with in vitro and in vivo experiments. Moreover, we screened the key molecule in ANXA10-induced CCA progression by mRNA sequencing and evaluated the correlation between PLA2G4A and ANXA10. The effect of PLA2G4A downstream signaling, including Cyclooxygenase 2, Prostaglandin E2(PGE2) and Signal transducer and activator of transcription 3(STAT3), on EMT and metastasis was further detected with in vitro and in vivo experiments. FINDINGS:ANXA10 expression was upregulated in PHCCA and DCCA but not in IHCCA. High ANXA10 expression was significantly associated with poor tumor differentiation and prognosis. ANXA10 promoted the proliferation, migration and invasion of the PHCCA cells. PLA2G4A expression was regulated by ANXA10 and high PLA2G4A predicted poor prognosis in PHCCA and DCCA. ANXA10 facilitated EMT and promoted metastasis by upregulating PLA2G4A expression, thus increasing PGE2 levels and activating STAT3. INTERPRETATION:ANXA10 was an independent prognostic biomarker of PHCCA and DCCA but not IHCCA. ANXA10 promoted the progression of PHCCA and facilitated metastasis by promoting the EMT process via the PLA2G4A/PGE2/STAT3 pathway. ANXA10, PLA2G4A and their downstream molecules, such as COX2 and PGE2, may be promising drug targets of PHCCA and DCCA.

Dataset Information

Gadd45? silencing impaired viability and metastatic phenotypes in cholangiocarcinoma cells by modulating the EMT pathway.

Publications

Gadd45β silencing impaired viability and metastatic phenotypes in cholangiocarcinoma cells by modulating the EMT pathway.

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