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MiR-382-3p downregulation contributes to the carcinogenesis of lung adenocarcinoma by promoting AKT SUMOylation and phosphorylation

ABSTRACT: Lung adenocarcinoma (LA), the primary histological type of non-small cell lung cancer, is still incurable; its diagnosis and treatment remain a major clinical challenge. A previous study by our group examined the microRNA (miRNA/miR) expression profile in the extracellular vesicles from patients with LA and healthy controls and indicated that miR-382-3p levels were reduced in patients with LA. However, the precise roles of miR-382-3p in LA have so far remained elusive. In the present study, the miR-382-3p levels in tumor and adjacent non-tumor control samples from 78 patients with LA were examined and it was identified that miR-382-3p expression was reduced in LA tumor samples compared with that in adjacent non-tumor control tissues (P=0.022). Furthermore, miR-382-3p overexpression inhibited LA growth in a xenograft mouse model. Prediction results indicated that miR-382-3p may regulate protein ubiquitination and SUMOylation. Small ubiquitin-like modifier (SUMO)1 activating enzyme subunit 1 (SAE1), one of the key components of the SUMO-activating complex, was identified as a direct target of miR-382-3p via dual-luciferase and immunoblotting assays. In patients with LA, miR-382-3p expression was negatively correlated with SAE1 protein levels (r=-0.39, P<0.05) and higher SAE1 expression contributed to poor prognosis (P<0.01). Using immunoprecipitation, it was identified that miR-382-3p reduction-induced SAE1 overexpression upregulated AKT SUMOylation, which further promoted AKT phosphorylation and activated the AKT signaling pathway. miR-382-3p inhibition promoted proliferation and inhibited apoptosis in LA cell lines, which was restored by SAE1 knockdown. In conclusion, the present study revealed that downregulation of miR-382-3p contributed to the carcinogenesis of LA via upregulation of SAE1 and promotion of AKT SUMOylation, providing a candidate target for LA treatment.

SUBMITTER: Fang H

PROVIDER: S-EPMC9185802 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Project description:BackgroundBone metastasis is a leading cause of morbidity and mortality in advanced prostate cancer (PCa). Downexpression of miR-133a-3p has been found to contribute to the progression, recurrence and distant metastasis in PCa. However, clinical significance of miR-133a-3p in bone metastasis of PCa, and the biological role of miR-133a-3p and its molecular mechanisms underlying bone metastasis of PCa remain unclear.MethodsmiR-133a-3p expression was evaluated in 245 clinical PCa tissues by real-time PCR. Statistical analysis was performed to evaluate the clinical correlation between miR-133a-3p expression and clinicopathological features, and overall and bone metastasis-free survival in PCa patients. The biological roles of miR-133a-3p in the bone metastasis of PCa were investigated both in vitro and in vivo. Bioinformatics analysis, real-time PCR, western blot and luciferase reporter analysis were applied to demonstrate the relationship between miR-133a-3p and its potential targets. Western blotting and luciferase assays were examined to identify the underlying pathway involved in the anti-tumor role of miR-133a-3p. Clinical correlation of miR-133a-3p with its targets was verified in human PCa tissues.ResultsmiR-133a-3p expression is reduced in PCa tissues compared with the adjacent normal tissues and benign prostate lesion tissues, particularly in bone metastatic PCa tissues. Low expression of miR-133a-3p is significantly correlated with advanced clinicopathological characteristics and shorter bone metastasis-free survival in PCa patients by statistical analysis. Moreover, upregulating miR-133a-3p inhibits cancer stem cell-like phenotypes in vitro and in vivo, as well as attenuates anoikis resistance in vitro in PCa cells. Importantly, administration of agomir-133a-3p greatly suppresses the incidence of PCa bone metastasis in vivo. Our results further demonstrate that miR-133a-3p suppresses bone metastasis of PCa via inhibiting PI3K/AKT signaling by directly targeting multiple cytokine receptors, including EGFR, FGFR1, IGF1R and MET. The negative clinical correlation of miR-133a-3p with EGFR, FGFR1, IGF1R, MET and PI3K/AKT signaling activity is determined in clinical PCa tissues.ConclusionOur results unveil a novel mechanism by which miR-133a-3p inhibits bone metastasis of PCa, providing the evidence that miR-133a-3p may serve as a potential bone metastasis marker in PCa, and delivery of agomir-133a-3p may be an effective anti-bone metastasis therapeutic strategy in PCa.

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MiR-382-3p downregulation contributes to the carcinogenesis of lung adenocarcinoma by promoting AKT SUMOylation and phosphorylation

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