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MiR-17 ~ 92 suppresses proliferation and invasion of cervical cancer cells by inhibiting cell cycle regulator Cdt2.

ABSTRACT: Cervical cancer (CC) is the 4th most leading cause of death among women worldwide, and if diagnosed in late stages the treatment options are almost negligible. 99% of CC is caused by high-risk human papilloma viruses (HR-HPV). Upon integration into human genome, the encoded viral proteins mis-regulate various onco-suppressors and checkpoint factors including cell cycle regulators. One such protein is cell cycle S phase licensing factor, CDC-10 dependent transcript-2 (Cdt2) which has been reported to be highly upregulated in various cancers including CC. Also, in CC cells, several tumor suppressor miRNAs are suppressed, including miR-17 ~ 92 cluster. In this study, we report that miR-17 ~ 92 directly recruits to 3'UTR of Cdt2 and downregulates this oncogene which suppresses the proliferation, migration and invasion capabilities of the CC cell lines without affecting non-cancerous cells. We further show that suppression of Cdt2 by miR-17 ~ 92, blocks the cancerous cells in S phase and induces apoptosis, eventually leading to their death. Hence, our work for the first time, mechanistically shows how miR-17 ~ 92 could work as tumor suppressor in cervical cancer cells, opening up the potential of miR-17 ~ 92 to be used in developing therapy for cervical cancer treatment.

SUBMITTER: Singh G

PROVIDER: S-EPMC10501107 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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miR-17 ~ 92 suppresses proliferation and invasion of cervical cancer cells by inhibiting cell cycle regulator Cdt2.

Singh Garima G Sharma Sonika Kumari SK Dorata Aastha A Singh Samarendra Kumar SK

Discover oncology 20230914 1

Cervical cancer (CC) is the 4th most leading cause of death among women worldwide, and if diagnosed in late stages the treatment options are almost negligible. 99% of CC is caused by high-risk human papilloma viruses (HR-HPV). Upon integration into human genome, the encoded viral proteins mis-regulate various onco-suppressors and checkpoint factors including cell cycle regulators. One such protein is cell cycle S phase licensing factor, CDC-10 dependent transcript-2 (Cdt2) which has been reporte ...[more]

PMID: 37707654

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Project description:BackgroundTriple-negative breast cancer (TNBC) is the malignancy with the worst outcome among all breast cancer subtypes. We reported that ETV1 is a significant oncogene in TNBC tumourigenesis. Consequently, investigating the critical regulatory microRNAs (miRNAs) of ETV1 may be beneficial for TNBC targeted therapy.MethodsWe performed in situ hybridization (ISH) and immunohistochemistry (IHC) to detect the location of miR-17-5p and ETV1 in TNBC patient samples, respectively. miR-17-5p expression in TNBC tissues and cell lines was assessed by quantitative real-time PCR (qRT-PCR). ETV1 expression was evaluated by qRT-PCR, western blotting and IHC. Cell Counting Kit-8 (CCK-8), colony formation, Transwell and wound closure assays were utilized to determine the TNBC cell proliferation and migration capabilities. In vivo tumour metastatic assays were performed in a zebra fish model.ResultsThe abundance of miR-17-5p was significantly decreased in TNBC cell lines and clinical TNBC tissues. The miR-17-5p expression levels were closely correlated with tumour size (P < 0.05) and TNM stage (P < 0.05). By contrast, the expression of ETV1 was significantly up-regulated in TNBC cell lines and tissues. There is an inverse correlation between the expression status of miR-17-5p and ETV1 (r = -0.28, P = 3.88 × 10-3). Luciferase reporter assay confirmed that ETV1 was a direct target of miR-17-5p. Forced expression of miR-17-5p in MDA-MB-231 or BT549 cells significantly decreased ETV1 expression and suppressed cell proliferation, migration in vitro and tumour metastasis in vivo. However, rescuing the expression of ETV1 in the presence of miR-17-5p significantly recovered the cell phenotype. High miR-17-5p expression was associated with a significantly favourable prognosis, in either the ETV1-positive or ETV1-negative groups (log-rank test, P < 0.001; P < 0.001). Both univariate and multivariate analyses showed that miR-17-5p and ETV1 were independent risk factors in the prognosis of TNBC patient.ConclusionsOur data indicate that miR-17-5p acts as a tumour suppressor in TNBC by targeting ETV1, and a low-abundance of miR-17-5p may be involved in the pathogenesis of TNBC. These findings indicate that miR-17-5p may be a therapeutic target for TNBC.

Dataset Information

MiR-17 ~ 92 suppresses proliferation and invasion of cervical cancer cells by inhibiting cell cycle regulator Cdt2.

Publications

miR-17 ~ 92 suppresses proliferation and invasion of cervical cancer cells by inhibiting cell cycle regulator Cdt2.

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