MicroRNA-93 inhibits tumor growth and early relapse of human colorectal cancer by affecting genes involved in the cell cycle

Although surgery remains the mainstay of curative treatment for colorectal cancer (CRC), many patients still have high chance to experience disease relapse. It is therefore imperative to identify prognostic markers that can help predict the clinical outcomes of CRC. Aberrant microRNA expression holds great potential as diagnostic and prognostic biomarker for CRC. Here we aimed to investigate clinical potential of miR-34a-5p as a prognostic marker for CRC recurrence and its functional significance. First, we validated that miR-34a-5p was downregulated in CRC tumour tissues (P<0.05). The expression level of tissue miR-34a-5p was then evaluated in two independent cohorts of 268 CRC patients. miR-34a-5p expression was positively correlated with disease-free survival in two independent cohorts (cohort I: n=205, P<0.001; cohort II: n=63, P=0.006). Moreover, the expression of miR-34a-5p was an independent prognostic factor for CRC recurrence by multivariate analysis (P<0.001 for cohort I, P=0.007 for cohort II). Ectopic expression of miR-34a-5p in p53 wild-type colon cancer cell HCT116 significantly inhibited cell growth, migration, invasion and metastasis. miR-34a-5p induced cell apoptosis, cell cycle arrest at G1 phase and p53 transcription activity in HCT116 cells, but not in the HCT116 p53 knockout (p53(-/-)) cells. miR-34a-5p significantly suppressed the HCT116 growth in vivo, whereas it showed no effect on the HCT116 p53(-/-) xenograft, indicating that the growth-inhibiting effect by miR-34a-5p was dependent on p53. In addition, the expression level of miR-34a-5p in patients with p53-positive expression was higher than that in patients with p53-negative expression (P<0.01). In conclusion, miR-34a-5p inhibits recurrence of CRC through inhibiting cell growth, migration and invasion, inducing cell apoptosis and cell cycle arrest in a p53-dependent manner.

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“…[27][28][29] Their results are complementary to ours and suggest that dysregulated miRNAs in tumours could predict recurrence of CRC.…”

Section: Discussionsupporting

confidence: 73%

miR-34a-5p suppresses colorectal cancer metastasis and predicts recurrence in patients with stage II/III colorectal cancer

et al. 2014

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“…*P < 0.05 vs. sham group; # P < 0.05 vs. I/R + miR control group Until now, studies of miR-93 have been focused mainly on its involvement in many types of human cancers, such as glioblastoma, gastric cancer, breast carcinoma, and others. miR-93 is overexpressed in a number of types of human cancers and functions as an oncogene by targeting important cancer-related genes [25][26][27][28][29], whereas, in some types of cancers miR-93 was down-regulated and repressed proliferation paradoxically [30,31]. However, the present study is the first to investigate its role in ischemia-induced cerebral injury.…”

Section: Mir-93 Antagomir Induced Ho-1 Expression Through Nrf2mentioning

confidence: 67%

MicroRNA-93 Downregulation Ameliorates Cerebral Ischemic Injury Through the Nrf2/HO-1 Defense Pathway

Wang

Liang

et al. 2016

Neurochem Res

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The present study was designed to evaluate the potential role of miR-93 in cerebral ischemic/reperfusion (I/R) injury in mice. The stroke model was produced in C57BL/6 J mice via middle cerebral artery occlusion (MCAO) for 1 h followed by reperfusion. And miR-93 antagomir was transfected to down-regulate the miR-93 level. Our results showed that miR-93 levels in the cerebral cortex of mice increased at 24 and 48 h after reperfusion. Importantly, in vivo study demonstrated that treatment with miR-93 antagomir reduced cerebral infarction volume, neural apoptosis and restored the neurological scores. In vitro study demonstrated that miR-93 antagomir attenuated hydrogen peroxide (HO)-induced injury. Moreover, miR-93 antagomir suppressed oxidative stress in I/R brain and HO treated cortical neurons. Furthermore, we founded that down-regulation of miR-93 increased the expression of nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase-1 (HO-1) and the luciferase reporter assay confirmed that miR-93 directly binds to the predicted 3'-UTR target sites of the nrf2 gene. Finally, we found that knockdown of Nrf2 or HO-1 abolished miR-93 antagomir-induced neuroprotection against oxidative stress in HO treated neuronal cultures. These results suggested that miR-93 antagomir alleviates ischemic injury through the Nrf2/HO-1 antioxidant pathway.

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“…Several previous studies have indicated that miR-93, miR-195, and members of the let-7 family of miRs are downregulated in lung cancer, CRC, and melanoma tissues as compared with normal tissue, suggesting that these miRs are tumor suppressors [29][30][31][32][33][34][35][36][37]. miR-93 can suppress the proliferation of human colon cancer cells and colon cancer stem cells, with worse OS being associated with low miR-93 expression in CRC patients [37,38].…”

Section: Discussionmentioning

confidence: 99%

Development of a deregulating MicroRNA panel for the detection of early relapse in postoperative colorectal cancer patients

Wang¹,

Yang²

2016

European Journal of Cancer

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MicroRNA-93 inhibits tumor growth and early relapse of human colorectal cancer by affecting genes involved in the cell cycle

Abstract: This study showed that microRNA-93 can inhibit tumorigenesis and reduce the recurrence of CRC; these findings may have potential clinical applications for predicting the recurrence of CRC.

Cited by 87 publications

References 42 publications

miR-34a-5p suppresses colorectal cancer metastasis and predicts recurrence in patients with stage II/III colorectal cancer

miR-34a-5p suppresses colorectal cancer metastasis and predicts recurrence in patients with stage II/III colorectal cancer

MicroRNA-93 Downregulation Ameliorates Cerebral Ischemic Injury Through the Nrf2/HO-1 Defense Pathway

Development of a deregulating MicroRNA panel for the detection of early relapse in postoperative colorectal cancer patients

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