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MicroRNA‑153‑3p suppresses retinoblastoma cell growth and invasion via targeting the IGF1R/Raf/MEK and IGF1R/PI3K/AKT signaling pathways.

ABSTRACT: Mounting evidence has demonstrated that microRNAs (miRNAs or miRs) play significant roles in various types of human tumors, including retinoblastoma (RB). However, the biological role and regulatory mechanisms of miRNAs in RB remain to be fully elucidated. The present study was designed to identify the regulatory effects of miRNAs in RB and the underlying mechanisms. Differentially expressed miRNAs in RB tissue were screened out based on the Gene Expression Omnibus (GEO) dataset, GSE7072, which revealed that miR‑153 in particular, displayed the highest fold change in expression. It was identified that miR‑153 was significantly downregulated in RB tissues, and its downregulation was closely associated with a larger tumor base and differentiation. Functional analysis revealed that the overexpression of miR‑153 inhibited RB cell proliferation, migration and invasion, and promoted the apoptosis of WERI‑RB‑1 and Y79 cells. In addition, insulin‑like growth factor 1 receptor (IGF1R) was identified as a target of miR‑153 in RB cells. More importantly, it was demonstrated that miR‑153 upregulation inhibited the expression of its target gene, IGF1R, which inhibited the activation of the Raf/MEK and PI3K/AKT signaling pathways. Collectively, the present study demonstrates for the first time, to the best of our knowledge, that miR‑153 functions as a tumor suppressor in RB by targeting the IGF1R/Raf/MEK and IGF1R/PI3K/AKT signaling pathways. Collectively, the findings presented herein demonstrate that miR‑153 targets IGF1R and blocks the activation of the Raf/MEK and PI3K/AKT signaling pathway, thus preventing the progression of RB. Thus, this miRNA may serve as a novel prognostic biomarker and therapeutic target for RB.

SUBMITTER: Guo L

PROVIDER: S-EPMC8143749 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We previously reported that relative to normal cervical mucus, microRNA 126‑3p (miR‑126‑3p) is present in significantly greater amounts in the cervical mucus of patients with overt cervical cancer or precursor lesions. Here, we investigated the effects of enforced miR‑126‑3p expression in the cervical cancer cell line, HeLa, on proliferation, migration, invasion, apoptosis and protein expression. We transfected HeLa cells with miR‑126‑3p miRNA and found that proliferation, migration and invasion by cell counting, wound healing, cell migration and invasion assay were significantly reduced in these cells relative to those transfected with a negative control mimic. The levels of phosphoinositide 3 kinase (PI3K), phosphorylated 3‑phosphoinositide‑dependent protein kinase‑1 (p‑PDK1) and p‑AKT proteins were lower in the miR‑126‑3p‑transfected cells. Phosphorylated 70S6K (p‑p70S6K), phosphorylated glycogen synthase kinase 3β (p‑GSK3β), phosphorylated S6K (p‑S6K), cyclin D1, phosphorylated p21‑activated kinase 1 (p‑PAK1), Rho associated coiled‑coil containing protein kinase 1 (ROCK1), myotonic dystrophy‑related CDC42‑binding kinases α (MRCKα) and phospholipase C γ1 (p‑PLCγ1) were also downregulated. This suggests that downstream effectors of the PI3K/PDK1/AKT pathway are targets for inhibition by miR‑126‑3p. In contrast, apoptotic‑related proteins including the BCL‑2‑associated agonist of cell death (Bad), B‑cell lymphoma‑extra‑large (Bcl‑xL) and BCL‑2‑associated X (Bax), were all upregulated by miR‑126‑3p, resulting in increased caspase 3/7 activity and apoptosis. Thus, enforced expression of miR‑126‑3p inhibited cell migration and invasion and also induced apoptosis by regulating the PI3K/PDK1/AKT pathway in HeLa cells. Hence, high levels of miR‑126‑3p may inhibit cervical carcinogenesis, and targeting the PI3K/PDK1/AKT pathway via miR‑126‑3p could represent a new approach for treating patients with cervical cancer.

Project description:BackgroundThe role of the membrane-associated RING-CH (MARCH) family in carcinogenesis has been widely studied, but the member of this family, RNF173, has not yet been thoroughly explored in the context of hepatocellular carcinoma (HCC).MethodsWith the use of an HCC tissue microarray and IHC staining, we aim to determine the differential expression of RNF173 in HCC patients and its clinical significance. The biological role of RNF173 is investigated through in vitro and in vivo experiments. RNA sequencing, mass spectrometry, and immunoprecipitation are performed to uncover the underlying mechanism of RNF173's impact on the development of HCC.ResultsThe mRNA and protein levels of RNF173 were significantly lower in HCC tissues than in normal tissues. HCC patients with low RNF173 expression had shorter overall survival and recurrence-free survival, and RNF173 was significantly correlated with tumor number, tumor capsule, tumor differentiation, and BCLC stage. In addition, in vitro and in vivo experiments showed that RNF173 downregulation exacerbated tumor progression, including migration, invasion, and proliferation. GRB2 is a key molecule in the RAF/MEK/ERK pathway. RNF173 inhibits the RAF/MEK/ERK signaling by ubiquitinating and degrading GRB2, thereby suppressing HCC cell proliferation, invasion and migration. Combining clinical samples, we found that HCC patients with high RNF173 and low GRB2 expression had the best prognosis.ConclusionRNF173 inhibits the invasion and metastasis of HCC by ubiquitinating and degrading GRB2, thereby suppressing the RAF/MEK/ERK signaling pathway. RNF173 is an independent risk factor for the survival and recurrence of HCC patients. RNF173 may serve as a novel prognostic molecule and potential therapeutic target for HCC. Video Abstract Graphical abstract Model of RNF173 on RAF/MEK/ERK signaling. RNF173 knockdown resulted in impaired ubiquitination and degradation of GRB2, leading to the activation of the RAF/MEK/ERK signaling pathway and promotion of invasion and metastasis in HCC cells.

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MicroRNA‑153‑3p suppresses retinoblastoma cell growth and invasion via targeting the IGF1R/Raf/MEK and IGF1R/PI3K/AKT signaling pathways.

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