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Influence of SHH/GLI1 axis on EMT mediated migration and invasion of breast cancer cells.

ABSTRACT: Sonic Hedgehog signaling is critical for breast morphogenesis and cancer. The present study was conducted to explore the influence of SHH/GLI1 axis on epithelial mesenchymal transition and invasion in breast cancer cells. SHH/GLI1 positive samples demonstrated high expression of Snail and Vimentin with relatively low expression of E-cadherin. Overexpression of Vimentin and Snail in SHH/GLI1 positive patients was also associated with poor overall survival. Interestingly, GANT61 (GLI1 inhibitor) exposure significantly reduced cell viability and induced apoptosis at 10?µM. Suppression of Hedgehog pathway either by CRISPR mediated SHH knock out or GANT61 altered regulation of EMT markers in breast cancer cells. Moreover, in-activation of SHH/GLI1 axis also significantly restricted cell migration and invasiveness. These findings suggest that targeting SHH/GLI1 axis alters expression of EMT markers and abrogates neoplastic invasion in breast cancer cells.

SUBMITTER: Riaz SK

PROVIDER: S-EPMC6488587 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Influence of SHH/GLI1 axis on EMT mediated migration and invasion of breast cancer cells.

Riaz Syeda Kiran SK Ke Yuepeng Y Wang Fen F Kayani Mahmood Akhtar MA Malik Muhammad Faraz Arshad MFA

Scientific reports 20190429 1

Sonic Hedgehog signaling is critical for breast morphogenesis and cancer. The present study was conducted to explore the influence of SHH/GLI1 axis on epithelial mesenchymal transition and invasion in breast cancer cells. SHH/GLI1 positive samples demonstrated high expression of Snail and Vimentin with relatively low expression of E-cadherin. Overexpression of Vimentin and Snail in SHH/GLI1 positive patients was also associated with poor overall survival. Interestingly, GANT61 (GLI1 inhibitor) e ...[more]

PMID: 31036836

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Project description:BackgroundThe previous investigations have identified that long non-coding RNA (lncRNAs) act as crucial regulators in gastric carcinoma. However, the function of lncRNA MIR4435-2HG in the modulation of gastric carcinoma remains elusive. Here, we aimed to explore the role of MIR4435-2HG in gastric carcinoma.MethodThe Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were applied to select the differently expressed lncRNAs in gastric carcinoma. The qRT-PCR was applied to analyze MIR4435-2HG expression in carcinoma tissues and cell lines. The effect of MIR4435-2HG on proliferation, invasion, migration, and apoptosis of gastric carcinoma cells was detected by Cell Counting Kit-8 (CCK-8) assays, transwell assays, and flow cytometry in vitro. A subcutaneous tumor model was constructed to examine the tumor growth of gastric carcinoma cells after knocking out MIR4435-2HG. RNA immunoprecipitation and luciferase reporting assays were applied to evaluate the interaction of MIR4435-2HG, miR-138-5p, and Sox4.ResultsThe bioinformatics analysis based on TCGA and GEO databases indicated that MIR4435-2HG was obviously elevated in gastric carcinoma samples. The qRT-PCR analysis revealed that MIR4435-2HG was upregulated in clinical gastric carcinoma tissues and cells. The high expression of MIR4435-2HG is associated with the poor survival rate of patients. The knockout of MIR4435-2HG could repress the proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) and accelerate the apoptosis of gastric carcinoma cells. Moreover, the deletion of MIR4435-2HG was able to attenuate the tumor growth in vivo. Mechanically, we identified that MIR4435-2HG enhanced Sox4 expression by directly interacting with miR-138-5p as a competitive endogenous RNA (ceRNA) in gastric carcinoma cells, in which Sox4 was targeted by miR-138-5p.ConclusionMIR4435-2HG is elevated in gastric carcinoma cells and contributes to the growth, metastasis, and EMT of gastric carcinoma cells by targeting miR-138-5p/Sox4 axis. MIR4435-2HG may be applied as a potential therapeutic target in gastric carcinoma.

Project description:BackgroundEstrogen receptor β (ERβ) has been reported to play an anti-cancer role in breast cancer, but the regulatory mechanism by which ERβ exerts this effect is not clear. Claudin-6 (CLDN6), a tight junction protein, acts as a tumor suppressor gene in breast cancer. Our previous studies have found that 17β-estradiol (E2) induces CLDN6 expression and inhibits MCF-7 cell migration and invasion, but the underlying molecular mechanisms are still unclear. In this study, we aimed to investigate the role of ERβ in this process and the regulatory mechanisms involved.MethodsPolymerase chain reaction (PCR) and western blot were used to characterize the effect of E2 on the expression of CLDN6 in breast cancer cells. Chromatin immunoprecipitation (ChIP) assays were carried out to confirm the interaction between ERβ and CLDN6. Dual luciferase reporter assays were used to detect the regulatory role of ERβ on the promoter activity of CLDN6. Wound healing and Transwell assays were used to examine the migration and invasion of breast cancer cells. Western blot, immunofluorescence and transmission electron microscopy (TEM) were performed to detect autophagy. Xenograft mouse models were used to explore the regulatory effect of the CLDN6-beclin1 axis on breast cancer metastasis. Immunohistochemistry (IHC) was used to detect ERβ/CLDN6/beclin1 expression in breast cancer patient samples.ResultsHere, E2 upregulated the expression of CLDN6, which was mediated by ERβ. ERβ regulated CLDN6 expression at the transcriptional level. ERβ inhibited the migration and invasion of breast cancer cells through CLDN6. Interestingly, this effect was associated with CLDN6-induced autophagy. CLDN6 positively regulated the expression of beclin1, which is a key regulator of autophagy. Beclin1 knockdown reversed CLDN6-induced autophagy and the inhibitory effect of CLDN6 on breast cancer metastasis. Moreover, ERβ and CLDN6 were positively correlated, and the expression of CLDN6 was positively correlated with beclin1 in breast cancer tissues.ConclusionOverall, this is the first study to demonstrate that the inhibitory effect of ERβ on the migration and invasion of breast cancer cells was mediated by CLDN6, which induced the beclin1-dependent autophagic cascade.

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Influence of SHH/GLI1 axis on EMT mediated migration and invasion of breast cancer cells.

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Influence of SHH/GLI1 axis on EMT mediated migration and invasion of breast cancer cells.

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