miR-182 and miR-183 Promote Cell Proliferation and Invasion by Targeting FOXO1 in Mesothelioma

Abstract

Dysregulation of miR-182 and miR-183 has been implicated in the progression of several human cancers. Our previous study showed that miR-182 and miR-183 are upregulated in malignant mesothelioma. However, their biological functions remain unclear. We performed in-situ hybridization to analyze the expression of miR-182 and miR-183 in human tissues. Functional analysis was performed by treatment of two mesothelioma cell lines (ACC-MESO1 and CRL-5915) with miR-182 and miR-183 inhibitors. RT-PCR and western blot analysis were conducted to analyze the expression of FOXO1, a known target of both miR-182 and miR-183. Mesothelioma cells treated with FOXO1 siRNA and miR-182/183 inhibitors were also analyzed by evaluating cell proliferation and invasion, as well as expression of FOXO1 and its downstream targets. We confirmed miR-182 expression in 25/29 cases and miR-183 expression in 29/29 cases of human mesothelioma tissue by in-situ hybridization. Notably, inhibition of miR-182 or miR-183 reduced cell proliferation, invasion, migration, and adhesion abilities of mesothelioma cells. Surprisingly, transfection with both miR-182 and miR-183 inhibitors showed even more effects on cell progression. Furthermore, FOXO1 was identified as a target of miR-182 and miR-183 in mesothelioma cells. Inhibition of miR-182 and miR-183 reduced cell proliferation ability via upregulation of FOXO1 and its downstream targets, namely, p27. Moreover, inhibition of miR-182 and miR-183 reduced the cell invasion properties of mesothelioma cells. Our findings indicated that miR-182 and miR-183 promote mesothelioma cell progression via downregulation of FOXO1 and p27. Targeting the miR-182/183—FOXO1 axis could serve as a novel treatment against malignant mesothelioma.

Inhibition of miR‑18a‑3p reduces proliferation of mesothelioma cells and sensitizes them to cisplatin

“…Johnson et al (22) found that a miR-137 mimic inhibited the proliferation, invasion, and migration of mesothelioma cells, and Williams et al (23) found that miR-13 reduced proliferation, and increased apoptosis and necrosis of mesothelioma cells by downregulating MCL1. Further, we demonstrated previously that miR-1 and miR-214 inhibited mesothelioma cell progression by suppressing PIM1 (11,24), and miR-182 and miR-183 promoted mesothelioma cell progression by suppressing FOXO1 (25).…”

Propofol inhibits proliferation and cisplatin resistance in ovarian cancer cells through regulating the microRNA‑374a/forkhead box O1 signaling axis

“…He et al (38) demonstrated that in human osteosarcoma, mir-374a enhanced cell growth by inhibiting downstream FOXO1 signaling, which is consistent with the results of the current study in human ovarian cancer cells. Furthermore, p27 is a CDK inhibitor that has a negative regulatory effect on proliferation and is a downstream target of FOXO1; consequently, FOXO1 inhibits cell proliferation by upregulating p27 (39)(40)(41)(42). The Bim protein belongs to the Bcl-2 protein family and exerts a pro-apoptotic effect on cells (43,44); previous studies have confirmed that FOXO1 regulates cell apoptosis through its downstream targets, including Bim (45,46).…”

MicroRNA‐182 exacerbates blood‐brain barrier (BBB) disruption by downregulating the mTOR/FOXO1 pathway in cerebral ischemia

“…Based on database predictions and previous reports, we hypothesized that mTOR and FOXO1 are two important downstream targets of miR-182. 15,47 Existing reports have shown that mTOR can protect cortical neurons by inhibiting apoptosis after OGD. 48 Of note, as an important transcription factor, FOXO1 deficiency causes a wide range of scar formation and infarct area accompanied by downregulation of the ratio of Bcl-2/ Bax following acute ischemia/reperfusion injury.…”