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DHRS2 inhibits cell growth and motility in esophageal squamous cell carcinoma.

ABSTRACT: Esophageal squamous cell carcinoma (ESCC) is highly prevailing in Asia and it is ranked in the most aggressive squamous cell carcinomas. High-frequency loss of heterozygosity occurred in chromosome 14q11.2 in many tumors including ESCC, suggesting that one or more tumor-suppressor genes might exist within this region. In this study, we identified the tumor-suppressing role of DHRS2 (short-chain dehydrogenase/reductase family, member 2) at 14q11.2 in ESCCs. Downregulation of DHRS2 occurred in 30.8% of primary ESCC tumor tissues vs paired non-tumorous tissues. DHRS2 downregulation was associated significantly with ESCC invasion, lymph nodes metastasis and clinical staging (P<0.001). Survival analysis revealed that DHRS2 downregulation was significantly associated with worse outcome of patients with ESCC. In vitro and in vivo studies indicated that both DHRS2 variants could suppress cell proliferation and cell motility. Moreover, we demonstrated that DHRS2 could reduce reactive oxygen species and decrease nicotinamide adenine dinucleotide phosphate (oxidized/reduced), increase p53 stability and decrease Rb phosphorylation; it also decreased p38 mitogen-activated protein kinase phosphorylation and matrix metalloproteinase 2. In summary, these findings demonstrated that DHRS2 had an important part in ESCC development and progression.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC5851108 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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DHRS2 inhibits cell growth and motility in esophageal squamous cell carcinoma.

Zhou Y Y Wang L L Ban X X Zeng T T Zhu Y Y Li M M Guan X-Y XY Li Y Y

Oncogene 20171106 8

Esophageal squamous cell carcinoma (ESCC) is highly prevailing in Asia and it is ranked in the most aggressive squamous cell carcinomas. High-frequency loss of heterozygosity occurred in chromosome 14q11.2 in many tumors including ESCC, suggesting that one or more tumor-suppressor genes might exist within this region. In this study, we identified the tumor-suppressing role of DHRS2 (short-chain dehydrogenase/reductase family, member 2) at 14q11.2 in ESCCs. Downregulation of DHRS2 occurred in 30. ...[more]

PMID: 29106393

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Project description:Purpose:Currently, the paucity of classical effective pharmacological drugs to treat esophageal squamous cell carcinoma (ESCC) is a major problem. The c-Myc (MYC) protein is a promising target as it is overexpressed in ESCC. MYC is a sensitive client protein of the heat shock protein 90 (HSP90) and, therefore, targeting the HSP90-MYC axis by inhibition of HSP90 is a potential therapeutic strategy for ESCC. Here, we evaluated the clinical application value of the HSP90 inhibitor (Ganetespib, STA-9090) as an anti-cancer agent for MYC-positive ESCC. Materials and Methods:We first analyzed ESCC tissue microarrays and clinical tissue samples to determine MYC expression. The relationship between MYC and HSP90 was analyzed by co-immunoprecipitation assays and immunofluorescence. In in vitro cell models, cell growth was analyzed using the CCK-8 kit, and MYC protein expression was analyzed by Western blot. The in vivo antitumor activity of STA-9090 was assessed in two xenograft animal models. Results:We demonstrated that MYC-overexpressing ESCC cells were highly sensitive to STA-9090 treatment through suppressing ESCC cell proliferation, cell cycle progression and survival. Moreover, STA-9090 treatment decreased MYC expression, reducing the half-life of the MYC protein. We further established two xenograft mouse models using ESCC cells and clinical ESCC samples to validate the effectiveness of STA-9090 in vivo. In both xenograft models, STA-9090 substantially inhibited the growth of MYC-positive ESCC tumors in vivo. In contrast, STA-9090 treatment demonstrated no bene?cial effects in mice with low-MYC expressing ESCC tumors. Conclusion:In conclusion, our data support that the HSP90 inhibitor, STA-9090, suppresses the expression of the MYC protein and interferes with HSP90-MYC protein-protein interaction. This, in turn, leads to inhibition of ESCC cell proliferation and promotion of apoptosis in ESCC cells in vitro and reduction of ESCC tumors in vivo. We propose, based on our findings, that STA-9090 is a potential novel therapeutic target for MYC-positive ESCC.

Dataset Information

DHRS2 inhibits cell growth and motility in esophageal squamous cell carcinoma.

Publications

DHRS2 inhibits cell growth and motility in esophageal squamous cell carcinoma.

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