Russian Journal of Genetics, volume 60, issue 11, pages 1556-1562

miR-17-5p Accelerates the Proliferation and Invasion of Colorectal Cancer via Regulating E2F1

Publication typeJournal Article
Publication date2024-11-25
scimago Q4
wos Q4
SJR0.185
CiteScore1.0
Impact factor0.6
ISSN10227954, 16083369
Abstract
miR-17-5p and E2F1 have been shown to have potential oncogenic effects in Colorectal Cancer (CRC) by bioinformatic approaches in our previous study. Building on these findings, we performed experimental validation and functional analysis of this miRNA and gene, which is critically important to CRC as diagnostics. This study considered the possible function of miR-17-5p and E2F1 in SW480 and SW620 cells. miR-17-5p mimic/inhibitor was transfected to SW620 cells to analyze epithelial-mesenchymal transition (EMT), cell proliferation, colony formation, and invasion for functional analysis. Furthermore, blood samples were gathered from CRC patients and healthy controls to compare miR-17-5p and E2F1 levels. Relative mRNA and protein levels were detected using RT-qPCR and ELISA, respectively. miR-17-5p was consistently upregulated in patients and cells compared to healthy controls and control cells. miR-17-5p stimulated the proliferation, colony formation, invasion, and EMT of SW620 cells. miR-17-5p also significantly induced the expression of E2F1; besides, miR-17-5p overexpression induced EMT with upregulation of ZEB-1, and downregulation of E-cadherin. E2F1 expression was also upregulated in CRC patients and cells and positively correlated with miR-17-5p expression level despite being a target gene. These results determined that miR-17-5p in CRC functions as an oncogenic miRNA, at least in part, by regulating E2F1 expression. They also may be able to act as novel noninvasive biomarkers for CRC detection.
Yu W., Wang J., Li C., Xuan M., Han S., Zhang Y., Liu P., Zhao Z.
Journal of Cancer scimago Q2 wos Q2 Open Access
2022-01-28 citations by CoLab: 16 Abstract  
MicroRNA (miRNA) can affect tumor progression by regulating cell proliferation, apoptosis and metastasis. A significant upregulation of miR-17-5p expression was found in colorectal cancer (CRC) tissues by miRNA microarray chip analysis. However, the underlying mechanism of miR-17-5p in CRC is still unclear. The mRNA expression of miR-17-5p was significantly higher in CRC tissues than in adjacent normal tissues. In CRC group, the expression of miR-17-5p in cancer tissues with lymph node metastasis was higher compared with those without lymph node metastasis. The biological function of miR-17-5p was demonstrated through CCK-8, colony formation, flow cytometry and transwell assays. Overexpression of miR-17-5p inhibited CRC cell apoptosis, as well as promoting proliferation, migration and invasion. Transcriptome sequencing and miRNA target prediction software suggested that HSPB2 might be a target gene of miR-17-5p and luciferase reporter detection validated for the first time that miR-17-5p binds directly to the 3'-UTR of HSPB2. In the rescue experiment, the tumor suppressive effect of HSPB2 was detected and miR-17-5p could promote cell proliferation, migration and invasion by targeting HSPB2. Taken together, miR-17-5p promotes invasion and migration by inhibiting HSPB2 in CRC, thereby implicating its potential as a novel diagnostic biomarker and therapeutic target for CRC.
Ma Y., Wang S., Bao J., Wang C.
2021-10-18 citations by CoLab: 1 Abstract  
E2Fs are important components of transcription factors and play key roles in occurrence or advancement of various cancers, but the expression and exact roles of each E2F in colorectal cancer (CRC) are rarely known. To address this issue, we investigated the roles and prognostic values of E2Fs expressions in CRC patients by searching ONCOMINE, cBioPortal, GEPIA, Matascape and UALCAN. E2F1, 3–8 were upregulated at the mRNA level and E2F2 was less expressed in CRC tissues than in normal tissues. The eight E2Fs were correlated with tumor stages of CRC. Survival analysis using GEPIA revealed that high expressions of E2F3, 4 were related with short overall survival in all CRC patients. The mutation rate of E2Fs (60%) was high and genetic alteration in E2Fs was linked with longer overall survival in CRC patients. Functional analysis implied that E2Fs and their 50 nearby genes were concentrated in tumor-related pathways. E2Fs may be candidate biomarkers for CRC diagnosis and E2F3, 4 are potential prognosis biomarkers of CRC. Nevertheless, our findings must be validated in the future to popularize the clinical application of E2Fs in CRC.
García-Martínez A., López-Muñoz B., Fajardo C., Cámara R., Lamas C., Silva-Ortega S., Aranda I., Picó A.
Diagnostics scimago Q2 wos Q1 Open Access
2020-04-16 citations by CoLab: 12 PDF Abstract  
miR-17-5p and E2F1 have been described as deregulated in cancer, but they have scarcely been studied in pituitary neuroendocrine tumours (PitNETs). This study evaluates the relationship of E2F1 and miR-17-5p with the invasiveness and proliferation of PitNETs. In this cross-sectional descriptive study, we evaluated the expression of E2F1, MYC, and miR-17-5p by quantitative real time PCR analysis in 60 PitNETs: 29 gonadotroph (GT), 15 functioning somatotroph (ST), and 16 corticotroph (CT) tumours, of which 8 were silent (sCT). The clinical data were collected from the Spanish Molecular Register of Pituitary Adenomas (REMAH) database. We defined invasiveness according to the Knosp classification and proliferation according to a molecular expression of Ki-67 ≥ 2.59. E2F1 was more expressed in invasive than in non-invasive tumours in the whole series (p = 0.004) and in STs (p = 0.01). In addition, it was overexpressed in the silent subtypes (GTs and sCTs; all macroadenomas) and normoexpressed in the functioning ones (fCTs and STs; some microadenomas). miR-17-5p was more expressed in proliferative than in non-proliferative tumours (p = 0.041) in the whole series but not by subtypes. Conclusions: Our study suggests that in PitNETs, E2F1 could be a good biomarker of invasiveness, and miR-17-5p of proliferation, helping the clinical management of these tumours.
Xu P., Wu Q., Yu J., Rao Y., Kou Z., Fang G., Shi X., Liu W., Han H.
Frontiers in Genetics scimago Q2 wos Q2 Open Access
2020-03-31 citations by CoLab: 59 PDF Abstract  
MicroRNAs (miRNAs) are a class of important noncoding RNAs, which play important roles in tumorigenesis and development by targeting oncogenes or tumor suppressor genes. One miRNA can regulate multiple genes, and one gene can be regulated by multiple miRNAs. To promote the clinical application of miRNAs, two fundamental questions should be answered: what's the regulatory mechanism of a miRNA to a gene, and which miRNAs are important for a specific type of cancer. In this study, we propose a miRNA influence capturing (MiRNAInf) to decipher regulation relations of miRNAs on target genes and identify critical miRNAs in cancers in a systematic approach. With the pair-wise miRNA/gene expression profiles data, we consider the assigning problem of a miRNA on target genes and determine the regulatory mechanisms by computing the Pearson correlation coefficient between the expression changes of a miRNA and that of its target gene. Furthermore, we compute the relative local influence strength of a miRNA on its target gene. Finally, integrate the local influence strength and target gene's importance to determine the critical miRNAs involved in specific cancer. Results on breast, liver and prostate cancers show that positive regulations are as common as negative regulations. The top-ranked miRNAs show great potential as therapeutic targets driving cancer to a normal state, and they are demonstrated to be closely related to cancers based on biological functional analysis, drug sensitivity/resistance analysis and survival analysis. This study will be helpful for the discovery of critical miRNAs and development of miRNAs-based clinical therapeutics.
Brenner D.R., Heer E., Sutherland R.L., Ruan Y., Tinmouth J., Heitman S.J., Hilsden R.J.
JAMA network open scimago Q1 wos Q1 Open Access
2019-07-31 citations by CoLab: 81 PDF Abstract  
Recent evidence has shown that although the incidence of colorectal cancer (CRC) is decreasing among older adults, rates have increased in adults younger than 50 years. Given that younger adults are typically classified as at low risk for the disease, this epidemiologic shift is cause for concern.To analyze Canadian national cancer incidence registries to determine incidence trends for CRC among older and younger adults, updated to 2015.This cohort study determined the incidence of CRC using data from the National Cancer Incidence Reporting System (1969-1992) and the Canadian Cancer Registry (1992-2015). All Canadians diagnosed with CRC from January 1, 1969, through December 31, 2015, were included in this study. Trends among men and women were examined separately and by age category (>50 vs
Tan H., Huang S., Zhang Z., Qian X., Sun P., Zhou X.
EBioMedicine scimago Q1 wos Q1 Open Access
2019-05-01 citations by CoLab: 58 Abstract  
While microRNAs (miRNAs) were widely considered to repress target genes at mRNA and/or protein levels, emerging evidence from in vitro experiments has shown that miRNAs can also activate gene expression in particular contexts. However, this counterintuitive observation has rarely been reported or interpreted in in vivo conditions.We systematically explored the positive correlation between miRNA and gene expressions and its potential implications in tumorigenesis, based on 8375 patient samples across 31 major human cancers from The Cancer Genome Atlas (TCGA).We found that positive miRNA-gene correlations are surprisingly prevalent and consistent across cancer types, and show distinct patterns than negative correlations. The top-ranked positive correlations are significantly involved in the immune cell differentiation and cell membrane signaling related processes, and display strong power in stratifying patients in terms of survival rate. Although intragenic miRNAs generally tend to co-express with their host genes, a substantial portion of miRNAs shows no obvious correlation with their host gene plausibly due to non-conservation. A miRNA can upregulate a gene by inhibiting its upstream suppressor, or shares transcription factors with that gene, both leading to positive correlation. The miRNA/gene sites associated with the top-ranked positive correlations are more likely to form super-enhancers compared to randomly chosen pairs. Wet-lab experiments revealed that positive correlations partially remain in in vitro condition.Our study brings new insights into the critical role of miRNA in gene regulation and the complex mechanisms underlying miRNA functions, and reveals both biological and clinical significance of miRNA-associated gene activation.
Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A.
2018-09-12 citations by CoLab: 58587 Abstract  
This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.
Fu F., Jiang W., Zhou L., Chen Z.
Translational Oncology scimago Q1 wos Q1 Open Access
2018-04-01 citations by CoLab: 162 Abstract  
Exosomes are extracellular membrane vesicles of 50- to 130-nm diameter secreted by most tumor cells. Exosomes can mediate the intercellular transfer of proteins and RNAs, including microRNAs (miRNAs), and promote both tumorigenesis and premetastatic niche formation. In this study, we performed exosomal RNA sequencing to identify candidate exosomal miRNAs that could be associated with colorectal cancer (CRC) and its distant metastasis. The expression profiles of exosomal miRNA, as secreted by isogenic human primary CRC cell line SW480 and highly metastatic cell line SW620, were analyzed and the potential targets related to tumorigenesis and metastatic progression were investigated. We found that 25 miRNAs had been up-regulated and 5 miRNAs had been down-regulated in exosomes purified from SW620 culture supernatant. Candidate miRNAs were further evaluated for CRC diagnosis using quantitative real-time polymerase chain reaction in CRC patients. Higher expression levels of circulating exosomal miR-17-5p and miR-92a-3p were significantly associated with pathologic stages and grades of the CRC patients. CONCLUSIONS: Circulating exosomal miR-17-5p and miR-92a-3p may provide a promising noninvasive prognostic biomarker for primary and metastatic CRC.
Røed Skårderud M., Polk A., Kjeldgaard Vistisen K., Larsen F.O., Nielsen D.L.
Cancer Treatment Reviews scimago Q1 wos Q1
2018-01-01 citations by CoLab: 50 Abstract  
Despite advances in the treatment of colorectal cancer, third-line treatment options are still limited. Regorafenib was approved in 2012 for the treatment of patients with metastatic colorectal cancer previously treated with approved standard therapy. The purpose of this review is to present existing clinical data on regorafenib.We systematically searched the PubMed and Embase databases, as well as ASCO and ESMO conference abstracts, for studies in English including ≥30 patients, evaluating the efficacy and safety of regorafenib in patients with metastatic colorectal cancer. A meta-analysis was conducted on the published, randomized phase III trials.24 eligible studies were included. In two phase III trials, regorafenib significantly increased overall survival (OS), progression free survival (PFS), and disease control rate when compared to placebo. Survival benefits of 1.4 and 2.5 months were presented. The meta-analysis indicated a significant greater treatment effect on OS (hazard ratio 0.67) and PFS (hazard ratio 0.40), compared to placebo. The non-randomized studies mostly supported these results. The most frequently reported adverse events were hand-foot-skin reaction (25%-86%), hypertension (11%-47%) and fatigue (2%-73%).Large phase III randomized trials indicate that regorafenib provides a benefit in OS and PFS when compared to placebo. Adverse events were common, but manageable and typical of multi-target tyrosine kinase inhibitors. Further research is needed to investigate alternative approaches to the dosing of regorafenib and to explore clinical and molecular biomarkers that can guide patient selection.
Fuccio L., Repici A., Hassan C., Ponchon T., Bhandari P., Jover R., Triantafyllou K., Mandolesi D., Frazzoni L., Bellisario C., Bazzoli F., Sharma P., Rösch T., Rex D.K.
Gut scimago Q1 wos Q1
2017-12-05 citations by CoLab: 65 Abstract  
ObjectiveEndoscopic submucosal dissection (ESD) aims to achieve en bloc resection of non-pedunculated colorectal adenomas which might be indicated in cases with superficial submucosal invasive cancers (SMIC), but the procedure is time consuming and complex. The prevalence of such cancers is not known but may determine the clinical necessity for ESD as opposed to the commonly used piecemeal mucosal resection (endoscopic mucosal resection) of colorectal adenomas. The main aim was to assess the prevalence of SMIC SM1 (ie, invasion ≤1000 µm or less than one-third of the submucosa) on colorectal lesions removed by ESD.DesignA literature review was conducted using electronic databases (up to March 2017) for colorectal ESD series reporting the histology of the dissected lesions.Results51 studies with data on 11 260 colorectal dissected lesions were included. Most resected lesions (82.2%; 95% CI 78.8% to 85.3%) were adenomas (low- and high-grade dysplasia, 26.8% and 55.4%, respectively). Overall, 15.7% were submucosal cancers, but only slightly more than half (8.0%; 95% CI 6.1% to 10.3%) had an infiltration depth of ≤1000 µm, providing a number needed to treat (NNT) to avoid one surgery of 12.5. Estimating an oncologically curative (R0; G1/2; L0/V0) resection rate of 75.3% (95% CI 52.2% to 89.4%) for malignant lesions, the prevalence of curative resection lowered to 6% (95% CI 4.2% to 7.2%) with an NNT of 16.7.ConclusionThe low prevalence of SMIC SM1 in lesions selected for ESD as well as the even lower rate of curative resection limits the clinical applicability of endoscopic en bloc resection. This calls for caution over an indiscriminate use of this technique in the resection of colorectal neoplasia.
Slattery M.L., Herrick J.S., Mullany L.E., Samowitz W.S., Sevens J.R., Sakoda L., Wolff R.K.
Genes Chromosomes and Cancer scimago Q2 wos Q2
2017-07-30 citations by CoLab: 66 Abstract  
Tumor suppressor genes (TSGs) and oncogenes (OG) are involved in carcinogenesis. MiRNAs also contribute to cellular pathways leading to cancer. We use data from 217 colorectal cancer (CRC) cases to evaluate differences in TSGs and OGs expression between paired CRC and normal mucosa and evaluate how TSGs and OGs are associated with miRNAs. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were used. We focus on genes most strongly associated with CRC (fold change (FC) of ≥1.5 or ≤0.67) that were statistically significant after adjustment for multiple comparisons. Of the 74 TSGs evaluated, 22 were associated with carcinoma/normal mucosa differential expression. Ten TSGs were up-regulated (FAM123B, RB1, TP53, RUNX1, MSH2, BRCA1, BRCA2, SOX9, NPM1, and RNF43); six TSGs were down-regulated (PAX5, IZKF1, GATA3, PRDM1, TET2, and CYLD); four were associated with MSI tumors (MLH1, PTCH1, and CEBPA down-regulated and MSH6 up-regulated); and two were associated with MSS tumors (PHF6 and ASXL1 up-regulated). Thirteen of these TSGs were associated with 44 miRNAs. Twenty-seven of the 59 OGs evaluated were dysregulated: 14 down-regulated (KLF4, BCL2, SSETBP1, FGFR2, TSHR, MPL, KIT, PDGFRA, GNA11, GATA2, FGFR3, AR, CSF1R, and JAK3), seven up-regulated (DNMT1, EZH2, PTPN11, SKP2, CCND1, MET, and MYC); three down-regulated for MSI (FLT3, CARD11, and ALK); two up-regulated for MSI (IDH2 and HRAS); and one up-regulated with MSS tumors (CTNNB1). These findings suggest possible co-regulatory function between TSGs, OGs, and miRNAs, involving both direct and indirect associations that operate through feedback and feedforward loops.
Chen N., Li W., Huang K., Yang W., Huang L., Cong T., Li Q., Qiu M.
Oncotarget scimago Q2 Open Access
2017-03-08 citations by CoLab: 31 Abstract  
Colorectal cancer (CRC) is one of the most common cancers worldwide. However, the prognostic and clinical value of platelet-lymphocyte ratio (PLR) in colorectal cancer was still unclear, which attracted more and more researchers' considerable attention. We performed a systematic review and meta-analysis to investigate the relationship between PLR and survival as well as clinical features of CRC update to September 2016. The hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) were calculated to access the association. We included 24 eligible studies with a total of 13719 patients. Elevated PLR predicted shorter overall survival (OS) (HR=1.47; 95%CI, 1.28-1.68; p
Yang F., Li Y., Xu L., Zhu Y., Gao H., Zhen L., Fang L.
OncoTargets and Therapy scimago Q2 wos Q3 Open Access
2017-01-31 citations by CoLab: 28 PDF Abstract  
MicroRNAs (miRNAs) have been shown to be involved in the initiation and progression of cancers in the literature. In this study, we aimed to evaluate the clinicopathological role of miR-17 in breast cancer.The expression of miR-17 was measured in 132 breast cancer tissues and paired adjacent normal tissues by using real-time quantitative polymerase chain reaction. The association between miR-17 expression levels and clinicopathological parameters was also analyzed. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and flow cytometry assays were used to investigate the role of miR-17 in the regulation of breast cancer cells.The expression of miR-17 was remarkably increased in breast cancer tissues and cell lines. Clinical association analysis revealed that a high expression of miR-17 was prominently associated with poor survival time in breast cancer. Overexpression of miR-17 promoted cell proliferation and induced tumor growth.Our findings clarified that the upregulation of miR-17 played a vital role in breast cancer progression and suggested that miR-17 could be used as a prognostic biomarker for breast cancer.
Rossella F., Gabriele G., Federica T., Michela A., Mario G., Gabriele P., Nicola F., Giancarlo F., Dapas B.
Current Drug Delivery scimago Q2 wos Q2
2016-05-27 citations by CoLab: 17 Abstract  
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related death. Because of the fast growth, early hepatic metastasis and the multidrug resistance, the five-year survival rate is very low. Thus, the understanding of its biology can significantly contribute in identifying valuable targets for novel therapeutic approaches. In this regard, E2F1 may represent an interesting candidate. E2F1 is a transcription factor implicated in the regulation of many cellular processes including cell proliferation and apoptosis. Whereas the involvement of E2F1 in HCC has been recognized, its ability to act as a proliferative and/or apoptotic factor in HCC has not yet been clarified and, in this regard, an active debate is ongoing. The definition of E2F1 role in HCC is not a trivial aspect as it can have significant consequences for the development of novel therapeutic options with E2F1 as target. In this review, we present data about the reported proliferative/apoptotic effects as well as the dual (combined proliferation and apoptosis) functions of E2F1 in HCC discussing the molecular basis for this behavior. The data available so far indicate that the proliferative and apoptotic functions of E2F1 in HCC may coexist but the proliferative effect seems to be more pronounced than the apoptotic one.

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