A Regulatory MDM4 Genetic Variant Locating in the Binding Sequence of Multiple MicroRNAs Contributes to Susceptibility of Small Cell Lung Cancer

Gao, Feng; Xiong, Xiangyu; Pan, Wenting; Yang, Xinyu; Zhou, Changchun; Yuan, Qipeng; Zhou, Lixin; Yang, Ming

doi:10.1371/journal.pone.0135647

Cited by 32 publications

(38 citation statements)

References 35 publications

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“…Furthermore, studies have shown that miR-191-5p and miR-887-3p can only inhibit the expression of MDM4 in small cell lung cancer cells with the C allele rather than A allele. 35 These Figure 4 In vivo inhibition of miR-887-3p suppresses tumor growth and promotes apoptosis. PANC-1 cells were inoculated subcutaneously into SCID mice.…”

Section: Discussionmentioning

confidence: 99%

<p>MiR-887-3p Negatively Regulates STARD13 and Promotes Pancreatic Cancer Progression</p>

Xu¹,

Zheng²

2020

CMAR

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Purpose: STARD13 is regulated by various miRNAs. However, there are relatively few reports describing the relationship between miRNAs and STARD13 in pancreatic cancer. Therefore, the aim of this study was to explore the relationship between miRNA and STARD13 in pancreatic cancer. Patients and Methods: By analyzing the data from Gene Expression Omnibus (GEO) database, the relationship between STARD13 expression and pancreatic cancer was explored. Then, through sequence alignment, the sequence complementary to miR-887-3p in the 3ʹUTR of STARD13 mRNA was found, mutated and cloned. Dual-luciferase reporter assay was used to test the relationship between STARD13 and miR-887-3p. Pancreatic cancer tumor tissue and its adjacent tissues collected, and the expression of STARD13 and miR-887-3p in pancreatic cancer tissues was analyzed by RT-qPCR. After, miR-887-3p and its inhibitor were transfected into PANC-1 cells to further confirm the regulatory relationship between miR-887-3 and STARD13 by RT-qPCR, and CCK-8, colony formation assays, cell cycle analysis, apoptosis detection and transwell analysis were used to detect changes of proliferation, apoptosis, migration and invasion in PANC-1 cells. Finally, through in vivo experiments, the effect of miR-887-3p on tumor growth was researched. Results: We found that STARD13 expression is lower in pancreatic cancer tissues, with the level of miR-887-3p being higher in these tissues. Pancreatic cancer patients with particularly low levels of STARD13 presented with a poor prognosis. MiR-887-3p negatively regulates the expression of STARD13. Increasing levels of miR-887-3p decreased the expression of STARD13, which promoted the proliferation, cell cycle process, cell migration and invasion, and inhibited the apoptosis of pancreatic cancer cells. Inhibition of miR-887-3p in SCID mice could inhibit tumor growth and promote tumor cell apoptosis. Conclusion: In conclusion, STARD13 is negatively regulated by miR-887-3p in pancreatic cancer. MiR-877-3p may act to promote cancer progression, and as such, it is a viable target for intervention and diagnostic development.

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Section: Discussionmentioning

confidence: 99%

<p>MiR-887-3p Negatively Regulates STARD13 and Promotes Pancreatic Cancer Progression</p>

Xu¹,

Zheng²

2020

CMAR

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“…One SNP, rs4245739, has been identified as a risk factor for several cancers, including esophageal cancer 16 , non-Hodgkin’s lymphoma 17 , prostate cancer 18 , lung cancer 19 , and ovarian cancer 20 . Rs4245739(A > C) has also been associated with susceptibility to breast cancer 21 , the most common cancer among women and the fifth leading cause of cancer mortality worldwide 22 , 23 .…”

Section: Introductionmentioning

confidence: 99%

Profile of the breast cancer susceptibility marker rs4245739 identifies a role for miRNAs

Anwar¹,

Wulaningsih²,

Watkins³

2017

Cancer Biology & Medicine

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Objective:To determine the influence of the single nucleotide polymorphism (SNP) rs4245739 on the binding and expression of microRNAs and subsequent MDM4 expression and the correlation of these factors with clinical determinants of ER-negative breast cancers. Methods:FindTar and miRanda were used to detect the manner in which potential microRNAs are affected by the SNP rs4245739-flanking sequence. RNA sequencing data for ER-negative breast cancer from The Cancer Genome Atlas (TCGA) were used to compare the expression of miR-184, miR-191, miR-193a, miR-378, and MDM4 in different rs4245739 genotypes. Results:Comparison of ER-negative cancer patients with and without the expression of miR-191 as well as profile microRNAs (miR-184, miR-191, miR-193a and miR-378 altogether) can differentiate the expression of MDM4 among different rs4245739 genotypes. Although simple genotyping alone did not reveal significant clinical relationships, the combination of genotyping and microRNA profiles was able to significantly differentiate individuals with larger tumor size and lower number of involved lymph nodes (P < 0.05) in the risk group (A allele). Conclusions:We present two novel methods to analyze SNPs within 3′UTRs that use: (i) a single miRNA marker expression and (ii) an expression profile of miRNAs predicted to bind to the SNP region. We demonstrate that the application of these two methods, in particular the miRNA profile approach, permits detection of new molecular and clinical features related to the rs4245739 variant in ER-negative breast cancer.

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“…Increased levels of miR-887 were previously reported in endometrial and rectal cancer (77,78). In contrast, other authors have demonstrated that miR-887 may act as a tumor suppressor in prostate cancer, breast cancer and small cell lung cancer (SCLC) (79)(80)(81). We have shown that mutations in miRNA genes and known cancer driver genes are not mutually exclusive, but a substantial number of miRNA gene mutations were identified in samples without mutations in known protein-coding drivers.…”

Section: Discussionmentioning

confidence: 62%

Somatic mutations in miRNA genes in lung cancer – potential functional consequences of non-coding sequence variants

Galka-Marciniak

Urbanek-Trzeciak

Nawrocka

et al. 2019

Preprint

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A growing body of evidence indicates that miRNAs may either drive or suppress oncogenesis. However, little is known about somatic mutations in miRNA genes. To determine the frequency and potential consequences of miRNA gene mutations, we analyzed whole exome sequencing datasets of ~500 lung adenocarcinoma (LUAD) and ~500 lung squamous cell carcinoma (LUSC) samples generated in the TCGA. Altogether, we identified >1000 mutations affecting ~500 different miRNA genes and showed that half of all cancers had at least one such mutation. Mutations occurred in most crucial parts of miRNA precursors, including mature miRNA and seed sequences. We showed that seed mutations strongly affected miRNA:target interactions, drastically changing the pool of predicted targets. Mutations may also affect miRNA biogenesis by changing the structure of miRNA precursors, DROSHA and DICER cleavage sites, and regulatory sequence/structure motifs. We identified 10 significantly overmutated hotspot miRNA genes, including the miR-379 gene in LUAD enriched in mutations in the mature miRNA and regulatory sequences. The occurrence of mutations in the hotspot miRNA genes was also shown experimentally. We present a comprehensive analysis of somatic mutations in miRNA genes and show that some of these genes are mutational hotspots, suggesting their potential role in cancer.3

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A Regulatory MDM4 Genetic Variant Locating in the Binding Sequence of Multiple MicroRNAs Contributes to Susceptibility of Small Cell Lung Cancer

Cited by 32 publications

References 35 publications

<p>MiR-887-3p Negatively Regulates STARD13 and Promotes Pancreatic Cancer Progression</p>

<p>MiR-887-3p Negatively Regulates STARD13 and Promotes Pancreatic Cancer Progression</p>

Profile of the breast cancer susceptibility marker rs4245739 identifies a role for miRNAs

Somatic mutations in miRNA genes in lung cancer – potential functional consequences of non-coding sequence variants

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