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Silencing of LINC00461 enhances radiosensitivity of lung adenocarcinoma cells by down-regulating HOXA10 via microRNA-195.

ABSTRACT: Lung adenocarcinoma is recognized as one of the most recurrent tumours in adults. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts and have been demonstrated to regulate biological functions during tumorigenesis. Our study aims to investigate the underlying molecular mechanisms of LINC00461/microRNA-195 (miR-195)/HOXA10 responsible for its involvement in lung adenocarcinoma. We firstly selected differentially expressed lncRNAs and genes by the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO). The functional role of LINC00461 in lung adenocarcinoma was then determined using ectopic expression, knockdown and reporter assay experiments. Besides, we detected the expression profiles of LINC00461, miR-195, HOXA10 and apoptosis- and invasion-related genes. Cell proliferation, migration and invasion were evaluated. In vivo tumour formation ability was analysed. Overexpressed LINC00461 and HOXA10 but down-regulated miR-195 were observed in primary and metastatic lung adenocarcinoma. LINC00461 negatively regulated miR-195, while miR-195 negatively regulated HOXA10. Forced LINC00461 expression decreased expression of miR-195 and Bax, increased expression of HOXA10, MMP-2, MMP-9 and Bcl-2, promoted cell proliferation, migration and invasion as well as tumour formation, and enhanced radiosensitivity of lung adenocarcinoma cells. However, these effects were reversed by lentivirus-mediated miR-195-forced expression, thereby suggesting that miR-195 could antagonize the harmful effect of LINC00461 on lung adenocarcinoma cells. Collectively, the present study provides evidence supporting the inhibitory effect of LINC00461 silencing on lung adenocarcinoma, which suppresses lung adenocarcinoma cell migration, invasion and radiosensitivity via HOXA10 by binding to miR-195, which provides a promising basis for the targeted intervention treatment for human lung adenocarcinoma.

SUBMITTER: Hou J

PROVIDER: S-EPMC7077533 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Silencing of LINC00461 enhances radiosensitivity of lung adenocarcinoma cells by down-regulating HOXA10 via microRNA-195.

Hou Jiqiu J Wang Yanjun Y Zhang Hongmei H Hu Yuxin Y Xin Xiuqin X Li Xiaodan X

Journal of cellular and molecular medicine 20200122 5

Lung adenocarcinoma is recognized as one of the most recurrent tumours in adults. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts and have been demonstrated to regulate biological functions during tumorigenesis. Our study aims to investigate the underlying molecular mechanisms of LINC00461/microRNA-195 (miR-195)/HOXA10 responsible for its involvement in lung adenocarcinoma. We firstly selected differentially expressed lncRNAs and genes by the Cancer Genome Atlas (TCGA) database ...[more]

PMID: 31967713

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Project description:BackgroundAs one of the most common malignancy, lung adenocarcinoma (LUAD) is characterized by low 5-year survival rate. This research aimed to investigate the effects of ribonucleotide reductase regulatory subunit M2 (RRM2) on malignant biological behaviors and activation of cGAS/STING pathway. We also explored the synergistic sensitization mechanisms of RRM2 and radiotherapy.MethodsBioinformatic tools were used to evaluate the clinical significance of RRM2 in LUAD patients. The roles of RRM2 in malignant phenotype and DNA damage in LUAD cells were investigated with cell proliferation, colony formation, immunofluorescence, modified Boyden chamber and comet assays. The mouse models were used to evaluate the biological significance of RRM2 in vivo. Cytotoxic T cell infiltration was evaluated via flow cytometric analysis and immunohistochemistry staining in C57BL/6 mice. We also explored the synergistic effects of RRM2 silencing and radiation on LUAD cells with apoptosis assay and immunoblotting in vitro.ResultsBioinformatic analysis revealed that RRM2 had diagnostic values for LUAD patients. Higher levels of RRM2 predicted worse prognosis. RRM2 silencing inhibited LUAD cell proliferation, invasion and migration. RRM2 knockdown induced S phase arrest and DNA damage. RRM2 silencing induced cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, and the downstream targets were regulated in a STING-dependent manner. Knockdown of RRM2 suppressed tumor growth in the xenograft tumor models. RRM2 deficiency increased CD8 + T cells in the tumor tissues and spleens. Furthermore, RRM2 silencing had synergistic effects with radiation on inhibiting cell proliferation and promoting apoptosis. Meanwhile, this combination promoted the activation of cGAS/STING signaling pathway synergistically, and simultaneously increased expression of IFNβ, CCL5 and CXCL10.ConclusionOur results demonstrated that RRM2 silencing had anti-tumor values and activated the cGAS/STING signaling pathway. RRM2 silencing increased CD8 + T cells infiltration. RRM2 silencing cooperated with radiation to inhibit LUAD cell proliferation, promote apoptosis and enhance the activation of cGAS/STING signaling pathway. RRM2 could be a promising target for tumor regression through cancer immunotherapy in LUAD.

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Silencing of LINC00461 enhances radiosensitivity of lung adenocarcinoma cells by down-regulating HOXA10 via microRNA-195.

Publications

Silencing of LINC00461 enhances radiosensitivity of lung adenocarcinoma cells by down-regulating HOXA10 via microRNA-195.

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