Novel tumor suppressor microRNA at frequently deleted chromosomal region 8p21 regulates Epidermal Growth Factor Receptor in prostate cancer

Bucay, Nathan; Sekhon, Kirandeep; Majid, Shahana; Yamamura, Soichiro; Shahryari, Varahram; Tabatabai, Z. Laura; Greene, Kirsten L.; Tanaka, Yuichiro; Dahiya, Rajvir; Deng, Guoren; Saini, Sharanjot

doi:10.18632/oncotarget.11865

Cited by 15 publications

(25 citation statements)

References 44 publications

(56 reference statements)

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“…in the cytoplasm and nucleoplasm, and reduced protein level in the nuclear matrix. 33 These findings suggest that the expression of exon 37,38 This triggered our interest to explore the association between the CNA status of PDLIM2 and its expression in ESCC. Using data in TCGA-ESCC, we found that PDLIM2 gene-level deletion is frequent and is associated with decreased gene expression, suggesting that DNA copy loss might be a mechanism of its down-regulation.…”

Section: Deletion Of This Domain Results In Increased Accumulation Ofmentioning

confidence: 99%

“…Some of the previously observed CNAs include amplification of 11q13.3 ( FGF4 ), 3p26.33 ( SOX2OT ), 8q24.21 ( MYC ), 14q21.1 ( FOXA1 ) and deletion of 9p21.3 ( CDKN2A ) . Some tumour suppressor genes in 8p21 were down‐regulated as a result of deleted chromosomal region, such as BNIP3L in breast and ovarian cancer and NKX3.1 and miR‐3622b in prostate cancer . This triggered our interest to explore the association between the CNA status of PDLIM2 and its expression in ESCC.…”

Section: Discussionmentioning

confidence: 99%

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Systematic profiling identifies PDLIM2 as a novel prognostic predictor for oesophageal squamous cell carcinoma (ESCC)

Song

et al. 2019

J Cellular Molecular Medi

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Till now, no appropriate biomarkers for high‐risk population screening and prognosis prediction have been identified for patients with oesophageal squamous cell carcinoma (ESCC). In this study, by the combined use of data from the Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas (TCGA)‐oesophageal carcinoma (ESCA), we aimed to screen dysregulated genes with prognostic value in ESCC and the genetic and epigenetic alterations underlying the dysregulation. About 222 genes that had at least fourfold change in ESCC compared with adjacent normal tissues were identified using the microarray data in GDS3838. Among these genes, only PDLIM2 was associated with nodal invasion and overall survival (OS) at the same time. The high PDLIM2 expression group had significantly longer OS and its expression was independently associated with better OS (HR: 0.64, 95% CI: 0.43‐0.95, P = 0.03), after adjustment for gender and pathologic stages. The expression of its exon 7/8/9/10 had the highest AUC value (0.724) and better prognostic value (HR: 0.43, 95% CI: 0.22‐0.83, P = 0.01) than total PDLIM2 expression. PDLIM2 DNA copy deletion was common in ESCC and was associated with decreased gene expression. The methylation status of two CpG sites (cg23696886 and cg20449614) in the proximal promoter region of PDLIM2 showed a moderate negative correlation with the gene expression in PDLIM2 copy neutral/amplification group. In conclusion, we infer that PDLIM2 expression might be a novel prognostic indicator for ESCC patients. Its exon 7/8/9/10 expression had the best prognostic value. Its down‐regulation might be associated with gene‐level copy deletion and promoter hypermethylation.

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Section: Deletion Of This Domain Results In Increased Accumulation Ofmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Systematic profiling identifies PDLIM2 as a novel prognostic predictor for oesophageal squamous cell carcinoma (ESCC)

Song

et al. 2019

J Cellular Molecular Medi

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“…A focused objective of our research is to understand the mechanistic role of this frequently deleted genomic region in PCa progression and metastasis. Toward this, we have proposed and validated a novel hypothesis that this region is associated with a set of microRNA genes-miR-3622a, miR-3622b miR-383-that play important causal roles in PCa progression, recurrence and metastasis (19)(20)(21). MicroRNAs (miRNAs) are small, endogenous RNAs that suppress gene expression post transcriptionally via sequencespecific interactions with the 3′-untranslated regions (3′-UTRs) of cognate mRNA targets (22).…”

Section: Introductionmentioning

confidence: 99%

Role of a novel race-related tumor suppressor microRNA located in frequently deleted chromosomal locus 8p21 in prostate cancer progression

et al. 2019

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Abstract The prostate cancer (PCa) genome is characterized by deletions of chromosome 8p21–22 region that increase significantly with tumor grade and are associated with poor prognosis. We proposed and validated a novel, paradigm-shifting hypothesis that this region is associated with a set of microRNA genes—miR-3622, miR-3622b, miR-383—that are lost in PCa and play important mechanistic roles in PCa progression and metastasis. Extending our hypothesis, in this study, we evaluated the role of a microRNA gene located in chromosome 8p—miR-4288—by employing clinical samples and cell lines. Our data suggests that (i) miR-4288 is widely downregulated in primary prostate tumors and cell lines; (ii) miR-4288 expression is lost in metastatic castration-resistant PCa; (ii) miR-4288 downregulation is race-related PCa alteration that is prevalent in Caucasian patients and not in African Americans; (iii) in Caucasians, miR-4288 was found to be associated with increasing tumor grade and high serum prostate-specific antigen, suggesting that miR-4288 downregulation/loss may be associated with tumor progression specifically in Caucasians; (iv) miR-4288 possess significant potential as a molecular biomarker to predict aggressiveness/metastasis; and (v) miR-4288 is anti-proliferative, is anti-invasive and inhibits epithelial-to-mesenchymal transition; and (vi) miR-4288 directly represses expression of metastasis/invasion-associated genes MMP16 and ROCK1. Thus, the present study demonstrates a tumor suppressor role for a novel miRNA located with a frequently lost region in PCa, strengthening our hypothesis that this locus is causally related to PCa disease progression via loss of microRNA genes. Our study suggests that miR-4288 may be a novel biomarker and therapeutic target, particularly in Caucasians.

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“…We recently reported a tumor suppressive role of miR-3622b in PCa via its regulation of epidermal growth factor receptor. 37 Towards deciphering the regulatory role of this miRNA cluster in PCa, we explored the role of miR-3622a in the present study and discovered its important regulatory role in PCa EMT. miR-3622a is a recently discovered miRNA gene that has not been studied.…”

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confidence: 99%

A novel microRNA regulator of prostate cancer epithelial–mesenchymal transition

et al. 2017

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The most frequent alteration in the prostate oncogenome is loss of chromosome (chr) 8p21 that has been associated with loss of NKX3.1 homeobox gene. Chr8p21 deletions increase significantly with tumor grade and are associated with poor prognosis in prostate cancer (PCa), suggesting critical involvement of this region in tumor progression. Recent studies suggest that apart from NKX3.1, this region harbors alternative tumor suppressors that are yet undefined. We proposed a novel, paradigm shifting hypothesis that this locus is associated with a miRNA gene cluster-miR-3622a/b- that plays a crucial suppressive role in PCa. Here we demonstrate the crucial role of miR-3622a in prostate cancer epithelial-to-mesenchymal transition (EMT). MicroRNA expression profiling in microdissected human PCa clinical tissues showed that miR-3622a expression is widely downregulated and is significantly correlated with poor survival outcome and tumor progression. To understand the functional significance of miR-3622a, knockdown and overexpression was performed using non-transformed prostate epithelial and PCa cell lines, respectively, followed by functional assays. Our data demonstrate that endogenous miR-3622a expression is vital to maintain the epithelial state of normal and untransformed prostate cells. miR-3622a expression inhibits EMT, progression and metastasis of PCa in vitro and in vivo. Further, we found that miR-3622a directly targets EMT effectors ZEB1 and SNAI2. In view of these data, we propose that frequent loss of miR-3622a at chr8p21 region leads to induction of EMT states that in turn, promotes PCa progression and metastasis. This study has potentially significant implications in the field of prostate cancer as it identifies an important miRNA component of a frequently lost chromosomal region with critical roles in prostate carcinogenesis which is a highly significant step towards understanding the mechanistic involvement of this locus. Also, our study indicates that miR-3622a is a novel PCa biomarker and potential drug target for developing therapeutic regimens against advanced PCa.

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Novel tumor suppressor microRNA at frequently deleted chromosomal region 8p21 regulates Epidermal Growth Factor Receptor in prostate cancer

Cited by 15 publications

References 44 publications

Systematic profiling identifies PDLIM2 as a novel prognostic predictor for oesophageal squamous cell carcinoma (ESCC)

Systematic profiling identifies PDLIM2 as a novel prognostic predictor for oesophageal squamous cell carcinoma (ESCC)

Role of a novel race-related tumor suppressor microRNA located in frequently deleted chromosomal locus 8p21 in prostate cancer progression

A novel microRNA regulator of prostate cancer epithelial–mesenchymal transition

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