MALAT1/miR-101-3p/MCL1 axis mediates cisplatin resistance in lung cancer

Wang, Huaqi; Wang, Li; Zhang, Guojun; Lu, Chenyang; Chu, Heying; Yang, Rui; Zhao, Guoqiang

doi:10.18632/oncotarget.23483

Cited by 53 publications

(35 citation statements)

References 39 publications

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“…Therefore, the aim of our study was to explore the functional mechanism of LINC00461 in lung adenocarcinoma in relation to HOXA10.Subsequently, the key findings obtained from this study provided evidence that LINC00461 silencing could potentially suppress lung adenocarcinoma cell migration, invasion while enhancing radiosensitivity via downregulation of HOXA10 by binding to miR-195.Initially, our findings demonstrated that LINC00461 was up-regulated in lung adenocarcinoma and the ectopic expression of LINC00461 stimulated lung adenocarcinoma cell proliferation, migration and invasion but inhibited radiosensitivity. LncRNA can potentially affect gene expression by regulating chromatin modifications, transcription and post-transcriptional mechanisms and can therefore regulate cell apoptosis, proliferation, metastasis and chemo-resistance 21. LncRNAs have been reported to be involved in the pathology of lung cancer 22.…”

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confidence: 99%

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

Hou

Wang

Zhang

et al. 2020

J Cellular Molecular Medi

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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.

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confidence: 99%

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

Hou

Wang

Zhang

et al. 2020

J Cellular Molecular Medi

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“…miR-101-3p is a member of the miR-101 family, and a recent study indicated that it has tumor suppressor effects in patients with NSCLC ( 16 ). However, to the best of our knowledge, a limited number of studies have addressed the association between miR-101-3p and adjuvant chemotherapy in patients with NSCLC ( 17 – 19 ).…”

Section: Introductionmentioning

confidence: 99%

Prognostic implications of decreased microRNA‑101‑3p expression in patients with non‑small cell lung cancer

et al. 2018

Oncol Lett

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To investigate the expression level of microRNA-101-3p (miR-101-3p) and its possible association with progression, prognosis and chemotherapy in patients with non-small cell lung cancer (NSCLC), the Gene Expression Omnibus (GEO) database was used. Quantitative polymerase chain reaction was used to verify the expression in 327 NSCLC and 42 adjacent normal lung tissues, of which 42 viable tissues were paired with nearby normal lung tissues. Based on the Cox regression model, univariate and multivariate analyses were used to address the factors that had effects on overall survival (OS) and disease-free survival (DFS) rate. Data from the GEO database demonstrated that the miR-101-3p expression in NSCLC was downregulated, compared with normal lung cancer. Survival analysis through univariate and multivariate models indicated that the miR-101-3p expression level was a crucial risk factor for OS and DFS in patients with NSCLC. A number of clinical parameters were determined to be associated with miR-101-3p expression, including tumor diameter, lymph node metastasis and tumor-node-metastasis stage. Adjuvant chemotherapy with high expression of miR-101-3p was determined to increase OS and DFS in patients with NSCLC, compared with patients with de novo or low expression of miR-101-3p. The present results demonstrated that miR-101-3p expression levels were associated with NSCLC progression and prognosis, which indicated that miR-101-3p may serve as a biomarker for patients with NSCLC who have received adjuvant chemotherapy.

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“…By combining novel MCL1 inhibitors with low dose cisplatin, we could potentially combat cisplatin resistance and/or decrease the therapeutic dosing. This rationale is supported by recent accounts that knockdown of MCL1 sensitizes cancer cells to cisplatin-induced apoptosis 65,66 .…”

Section: Discussionmentioning

confidence: 71%

MCL1 binds and negatively regulates the transcriptional function of tumor suppressor p73

et al. 2020

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MCL1, an anti-apoptotic protein that controls chemosensitivity and cell fate through its regulation of intrinsic apoptosis, has been identified as a high-impact target in anti-cancer therapeutic development. With MCL1-specific inhibitors currently in clinical trials, it is imperative that we understand the roles that MCL1 plays in cells, especially when targeting the Bcl-2 homology 3 (BH3) pocket, the central region of MCL1 that mediates apoptotic regulation. Here, we establish that MCL1 has a direct role in controlling p73 transcriptional activity, which modulates target genes associated with DNA damage response, apoptosis, and cell cycle progression. This interaction is mediated through the reverse BH3 (rBH3) motif in the p73 tetramerization domain, which restricts p73 assembly on DNA. Here, we provide a novel mechanism for protein-level regulation of p73 transcriptional activity by MCL1, while also framing a foundation for studying MCL1 inhibitors in combination with platinum-based chemotherapeutics. More broadly, this work expands the role of Bcl-2 family signaling beyond cell fate regulation.

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MALAT1/miR-101-3p/MCL1 axis mediates cisplatin resistance in lung cancer

Cited by 53 publications

References 39 publications

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

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

Prognostic implications of decreased microRNA‑101‑3p expression in patients with non‑small cell lung cancer

MCL1 binds and negatively regulates the transcriptional function of tumor suppressor p73

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