Epigenetically Deregulated microRNA-375 Is Involved in a Positive Feedback Loop with Estrogen Receptor α in Breast Cancer Cells

Simonini, Pedro de Souza Rocha; Breiling, Achim; Gupta, N. Vishal; Malekpour, Mahdi; Youns, Mаhmoud; Omranipour, Ramesh; Malekpour, Fatemeh; Volinia, Stefano; Croce, Carlo M.; Najmabadi, Hossein; Diederichs, Sven; Şahin, Özgür; Mayer, Doris; Lyko, Frank; Hoheisel, Jörg D.; Riazalhosseini, Yasser

doi:10.1158/0008-5472.can-10-1318

Cited by 266 publications

(222 citation statements)

References 48 publications

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“…Although several studies did not notice an upregulation of miR-375 in prostate carcinoma samples, various studies observed increased levels of this miRNA in prostate cancer serum samples (44,45). Publications confirm that miR-375 is downregulated in other cancer types such as cervical, lung, or head and neck carcinoma, as well as glioma (46)(47)(48)(49)(50) but upregulated in breast carcinoma (51). Likewise, miR-15a was previously shown to be downregulated in metastasizing prostate carcinoma (18).…”

Section: Discussionmentioning

confidence: 80%

Comparative microRNA Profiling of Prostate Carcinomas with Increasing Tumor Stage by Deep Sequencing

Hart

Nolte

Wach

et al. 2014

Molecular Cancer Research

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MicroRNAs (miRNA) posttranscriptionally regulate gene expression and are important in tumorigenesis. Previous deep sequencing identified the miRNA profile of prostate carcinoma versus nonmalignant prostate tissue. Here, we generated miRNA expression profiles of prostate carcinoma by deep sequencing, with increasing tumor stage relative to corresponding nonmalignant and healthy prostate tissue, and detected clearly changed miRNA expression patterns. The miRNA profiles of the healthy and nonmalignant tissues were consistent with our previous findings, indicating a high fidelity of the method employed. In the tumors, quantitative real-time PCR (qRT-PCR) analysis of 40 paired samples of prostate carcinoma versus normal tissue revealed significant upregulation of miR-20a, miR-148a, miR-200b, and miR-375 and downregulation of miR-143 and miR-145. Hereby, miR-375 increased from normal to organ-confined tumors (pT2 pN0), slightly decreased in tumors with extracapsular growth (pT3 pN0), but was then expressed again at higher levels in lymph node metastasizing (pN1) tumors. The sequencing data for miR-375 were confirmed by Northern blotting and qRT-PCR. The regulation for other selected miRNAs could, however, not be confirmed by qRT-PCR in individual tumor stages. MiR-200b, in addition to miR-200c and miR-375 reduced the expression of SEC23A. Interestingly, miR-375, found by sequencing in pT2 upregulated by us and others in tumor versus normal tissue, and miR-15a, found by sequencing in pT2 and pT3 and in the metastasizing tumors, target the phosphatases PHLPP1 and PHLPP2, respectively. PHLPP1 and PHLPP2 dephosphorylate members of the AKT family of signal transducers, thereby inhibiting cell growth. Coexpression of miR-15a and miR-375 resulted in downregulation of PHLPP1/2 and strongly increased prostate carcinoma cell growth.Implications: These genomic data reveal relevant miRNAs in prostate cancer that may have biomarker and therapeutic potential. Mol Cancer Res; 12(2); 250-63. Ó2013 AACR. IntroductionProstate carcinoma is the second most frequently diagnosed malignancy and a leading cause of cancer-related death in men worldwide (1). The underlying mechanisms resulting in invasive growth after dissemination of the primary tumor from the initial site in the prostate are not completely understood. MicroRNAs (miRNAs) are now recognized as contributing factors to the induction, growth, and metastasis

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Section: Discussionmentioning

confidence: 80%

Comparative microRNA Profiling of Prostate Carcinomas with Increasing Tumor Stage by Deep Sequencing

Hart

Nolte

Wach

et al. 2014

Molecular Cancer Research

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“…In breast cancer, higher expression of miR-375 in ERa-positive breast cell lines was shown to influence cell proliferation, and miR-375 overexpression caused loss of epigenetic marks including H3K9me2 and local DNA hypomethylation. Inhibition of miR-375 in ERa-positive MCF-7 cells reduced both ERa activation and cell proliferation [35]. In gastric cancer, miRNA-375 was found to be the most down-regulated miRNA, and ectopic expression of miRNA-375 in gastric carcinoma cells markedly reduced cell viability by a mechanism involving the caspase-mediated apoptosis pathway [37].…”

Section: Discussionmentioning

confidence: 96%

“…Recently, miR-375 hypermethylation was reported in breast cancer and gastric cancer [35,36]. In breast cancer, higher expression of miR-375 in ERa-positive breast cell lines was shown to influence cell proliferation, and miR-375 overexpression caused loss of epigenetic marks including H3K9me2 and local DNA hypomethylation.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic regulation of microRNA‐375 and its role in melanoma development in humans

et al. 2011

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Edited by Tamas Dalmay Keywords:Epigenetic regulation MicroRNA miR-375 Cell invasion Human melanoma a b s t r a c tTo identify epigenetically regulated miRNAs in melanoma, we treated a stage 3 melanoma cell line WM1552C, with 5AzadC and/or 4-PBA. Several hypermethylated miRNAs were detected, one of which, miR-375, was highly methylated and was studied further. Minimal CpG island methylation was observed in melanocytes, keratinocytes, normal skin, and nevus but hypermethylation was observed in patient tissue samples from primary, regional, distant, and nodular metastatic melanoma. Ectopic expression of miR-375 inhibited melanoma cell proliferation, invasion, and cell motility, and induced cell shape changes, strongly suggesting that miR-375 may have an important function in the development and progression of human melanomas.

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“…We found elevated miR-375 levels in SBNETs, which is also more often downregulated in cancers. However, high expression of miR-375 has been seen in ERα-positive breast cell lines and it is a key driver of their proliferation (de Souza Rocha Simonini et al 2010).…”

Section: Global Mirna Profiling Reveals a Signature Specific For Smalmentioning

confidence: 99%

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

Miller¹,

Frampton²,

Malczewska³

et al. 2016

Endocrine-Related Cancer

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Novel molecular analytes are needed in small bowel neuroendocrine tumours (SBNETs) to better determine disease aggressiveness and predict treatment response. In this study, we aimed to profile the global miRNome of SBNETs, and identify microRNAs (miRNAs) involved in tumour progression for use as potential biomarkers. Two independent miRNA profiling experiments were performed (n = 90), including primary SBNETs (n = 28), adjacent normal small bowel (NSB; n = 14), matched lymph node (LN) metastases (n = 24), normal LNs (n = 7), normal liver (n = 2) and liver metastases (n = 15). We then evaluated potentially targeted genes by performing integrated computational analyses. We discovered 39 miRNAs significantly deregulated in SBNETs compared with adjacent NSB. The most upregulated (miR-204-5p, miR-7-5p and miR-375) were confirmed by qRT-PCR. Two miRNAs (miR-1 and miR-143-3p) were significantly downregulated in LN and liver metastases compared with primary tumours. Furthermore, we identified upregulated gene targets for miR-1 and miR-143-3p in an existing SBNET dataset, which could contribute to disease progression, and show that these miRNAs directly regulate FOSB and NUAK2 oncogenes. Our study represents the largest global miRNA profiling of SBNETs using matched primary tumour and metastatic samples. We revealed novel miRNAs deregulated during SBNET disease progression, and important miRNA-mRNA interactions. These miRNAs have the potential to act as biomarkers for patient stratification and may also be able to guide treatment decisions. Further experiments to define molecular mechanisms and validate these miRNAs in larger tissue cohorts and in biofluids are now warranted.

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Epigenetically Deregulated microRNA-375 Is Involved in a Positive Feedback Loop with Estrogen Receptor α in Breast Cancer Cells

Cited by 266 publications

References 48 publications

Comparative microRNA Profiling of Prostate Carcinomas with Increasing Tumor Stage by Deep Sequencing

Comparative microRNA Profiling of Prostate Carcinomas with Increasing Tumor Stage by Deep Sequencing

Epigenetic regulation of microRNA‐375 and its role in melanoma development in humans

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

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