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Epigenetic silencing of IGFBPL1 promotes esophageal cancer growth by activating PI3K-AKT signaling.

ABSTRACT: BACKGROUND:There are seven insulin-like growth factor binding proteins (IGFBPs) that bind insulin-like growth factors (IGFs). IGFBP like protein1 (IGFBPL1) is a new member of this family. The function and mechanism of IGFBPL1 in esophageal cancer remains to be elucidated. METHODS:Eight esophageal cancer cell lines, 114 cases of esophageal dysplasia, and 501 cases of primary esophageal cancer samples were examined in this study. Methylation-specific polymerase chain reaction (MSP), immunohistochemistry, Western blot, flow cytometry, RNA interference assay, and xenograft mouse models were employed. RESULTS:The expression of IGFBPL1was lost and complete methylation was found in KYSE150 and KYSE410 cells. Reduced expression and partial methylation of IGFBPL1 was found in Bic1, KYSE140, KYSE450, KYSE520, and COLO680N cells. High expression and unmethylation was detected in KYSE510 cells. Restoration of IGFBPL1 expression was found in KYSE150 and KYSE410 cells and the expression of IGFBPL1 was increased in Bic1, KYSE140, KYSE450, KYSE520, and COLO680N cells, after 5-AZA-2'-deoxycytidine treatment. IGFBPL1 was methylated in 47.3% (53/114) of esophageal dysplasia and 49.1% (246/501) of human primary esophageal squamous cell carcinoma (ESCC). Methylation of IGFBPL1 was significantly associated with TNM stage (p?=?0.012), and tumor size (p?=?0.009). IGFBPL1 inhibited esophageal cancer cell clonal formation and proliferation and induced cell apoptosis and G1/S phase arrest. Further study found that IGFBPL1 is involved in PI3K-AKT signaling and IGFBPL1 suppressed human ESCC xenografts growth in mice. CONCLUSION:IGFBPL1 suppresses esophageal cancer cell growth by inhibiting PI3K-AKT signaling in vitro and in vivo. IGFBPL1 is a novel tumor suppressor in human esophageal cancer.

SUBMITTER: Liu Y

PROVIDER: S-EPMC7011530 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Epigenetic silencing of IGFBPL1 promotes esophageal cancer growth by activating PI3K-AKT signaling.

Liu Yingge Y Zhang Meiying M He Tao T Yang Weili W Wang Lidong L Zhang Lirong L Guo Mingzhou M

Clinical epigenetics 20200210 1

<h4>Background</h4>There are seven insulin-like growth factor binding proteins (IGFBPs) that bind insulin-like growth factors (IGFs). IGFBP like protein1 (IGFBPL1) is a new member of this family. The function and mechanism of IGFBPL1 in esophageal cancer remains to be elucidated.<h4>Methods</h4>Eight esophageal cancer cell lines, 114 cases of esophageal dysplasia, and 501 cases of primary esophageal cancer samples were examined in this study. Methylation-specific polymerase chain reaction (MSP), ...[more]

PMID: 32041673

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Project description:BackgroundThe human ether a-go-go-related gene 1 (HERG1) is involved in tumor progression; however, its role in esophageal squamous cell carcinoma (ESCC) is not well studied. This study investigated HERG1 function in ESCC progression and elucidated the underlying mechanisms.MethodsThe prognostic value of HERG1 was determined by immunohistochemistry in ESCC biopsies. Cell growth and proliferation were analyzed by colony formation and methyl thiazolyl tetrazolium assays. Cell migration and invasion were analyzed by wound healing and Boyden transwell assays. Epithelial-mesenchymal transition (EMT) was evaluated by immunoblotting and quantitative polymerase chain reaction (qPCR). A xenograft mouse model was used to validate the tumorigenic and metastatic roles of HERG1 in vivo.ResultsHERG1 expression was overall higher in ESCC tissues compared to adjacent non-tumor tissues. A retrospective analysis of 349 patients with ESCC (stages I-IV) confirmed increased HERG1 expression was associated with disease progression and higher mortality rate. The overall survival of the patients was significantly worse when their tumors displayed higher HERG1 expression. HERG1 knockdown reduced tumor growth and metastasis in athymic mice. HERG1 affected the proliferation, migration, and invasion of two ESCC cell lines (TE-1 and KYSE-30). Changes in HERG1 expression affected the expression of cell cycle- and EMT-related proteins; these effects were reversed by altering the expression of thioredoxin domain-containing protein 5 (TXNDC5), which is also associated with the clinicopathological characteristics of patients with ESCC and is relevant to HERG1 in pathological biopsies. Additionally, HERG1 expression altered phosphoinositide 3-kinase (PI3K) and AKT phosphorylation, thereby affecting TXNDC5 expression.ConclusionsHERG1 contributes to poor prognosis in patients with ESCC by promoting ESCC cell proliferation, migration, and invasion via TXNDC5 through the PI3K/AKT signaling pathway. Our findings provided novel insights into the pathology of ESCC and role of HERG1 in tumor progression, suggesting that targeting HERG1 has potential diagnostic and therapeutic value for ESCC treatment.

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Epigenetic silencing of IGFBPL1 promotes esophageal cancer growth by activating PI3K-AKT signaling.

Publications

Epigenetic silencing of IGFBPL1 promotes esophageal cancer growth by activating PI3K-AKT signaling.

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