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The (pro)renin receptor: a novel biomarker and potential therapeutic target for various cancers.

ABSTRACT: BACKGROUND:The (pro) renin receptor ((P)RR) plays important roles in various pathways, such as the Wnt/?-catenin, renin-angiotensin system (RAS), MAPK/ERK and PI3K/AKT/mTOR pathways, that are involved in a wide range of physiological and pathological processes incorporating the tumorigenesis. However, our knowledge about (P) RR was mostly limited to its roles in cardiovascular and renal physiological functions and diseases. In the past 5?years, however, compelling evidence has revealed that (P) RR is aberrantly expressed in and contributes to the development of various cancers by different means. For instance, (P) RR was recently demonstrated to induce the oncogenesis of pancreatic, colorectal and brain cancers via the Wnt signaling, while promote the endometrial cancer and glioblastoma through the RAS. METHODS:Combining with the deep analysis of big data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, this review updates and summarizes the recent studies about the newly recognized roles of (P) RR in the pathophysiological processes of cancer development and its detailed functions through related pathways, as well as the novel research progress of (P) RR in related fields including the development and application of soluble (P) RR detection kit and monoclonal (P) RR antibody. RESULTS:This review provides an overview of the essential roles of (P) RR in the tumorigenesis and progression of various cancers and offers a translational outlook for the future research and clinical practices. CONCLUSION:(P) RR in the tumor tissues and/or body fluids of patients may be a novel and promising biomarker and potential therapeutic target for diagnosis, treatment and prognosis prediction in various cancers. Video Abstract.

SUBMITTER: Wang J

PROVIDER: S-EPMC7060546 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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The (pro)renin receptor: a novel biomarker and potential therapeutic target for various cancers.

Wang Juan J Nishiyama Akira A Matsuyama Makoto M Wang Zhiyu Z Yuan Ying Y

Cell communication and signaling : CCS 20200306 1

<h4>Background</h4>The (pro) renin receptor ((P)RR) plays important roles in various pathways, such as the Wnt/β-catenin, renin-angiotensin system (RAS), MAPK/ERK and PI3K/AKT/mTOR pathways, that are involved in a wide range of physiological and pathological processes incorporating the tumorigenesis. However, our knowledge about (P) RR was mostly limited to its roles in cardiovascular and renal physiological functions and diseases. In the past 5 years, however, compelling evidence has revealed t ...[more]

PMID: 32143717

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Project description:BackgroundAccumulating studies indicated that dysregulated long non-coding RNA human histocompatibility leukocyte antigen (HLA) Complex P5 (HCP5) may functions as an potential prognostic predictor in multiple cancers. This meta-analysis was performed to systematically collect studies and conduct an evidence-based evaluation of the prognostic role of HCP5 in malignancies.MethodsFour databases (PubMed, Web of Science, Embase and Cochrane library) were comprehensively retrieved from their initiation date to November 9, 2021. Hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) were used to assess the associations between the expression level of HCP5 and prognosis or clinical characteristics. Moreover, results were validated by Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and the National Genomics Data Center (NGDC). Subsequently, the molecular mechanism of HCP5 was predicted based on MEM and StarBase databases. The study protocol was registered at PROSPERO (ID: CRD42021274208).Results9 studies, containing 641 patients, were included in this meta-analysis. Our results revealed that HCP5 overexpression was associated with poor overall survival (OS), tumor type, histological differentiation, and lymph node metastasis in most cancers, but was not associated with age, gender and tumor size; down-regulation of HCP5 was associated with worse OS, advanced tumor stage, positive distal metastasis and lymph node metastasis in skin cutaneous melanoma (SKCM). HCP5 was significantly up-regulated in four cancers and down-regulated in SKCM, which was validated by the GEPIA2 cohort. HCP5 expression in various types of cancer was also verified in NGDC. Further functional prediction revealed that HCP5 may participate in some cancer-related pathways.ConclusionThere is a significantly association between dysregulation of HCP5 and both prognosis and clinicopathological features in various cancers. HCP5 may be functions as a novel potential prognostic biomarker and therapeutic target in multiple human cancers.

Project description:IntroductionPI3K/AKT signaling pathway is upregulated in a broad spectrum of cancers. Among the class I PI3Ks (PI3Kδ/β/δ isoforms), PI3Kδ has been implicated in hematologic cancers and solid tumors. Alternative splicing is a post-transcriptional process for acquiring proteomic diversity in eukaryotic cells. Emerging evidence has highlighted the involvement of aberrant mRNA splicing in cancer development/progression.MethodsOur previous studies revealed that PIK3CD-S is an oncogenic splice variant that promotes tumor aggressiveness and drug resistance in prostate cancer (PCa). To further evaluate the potential of utilizing PI3Kδ-S (encoded from PIK3CD-S) as a cancer biomarker and/or drug target, comprehensive analyses were performed in a series of patient samples and cell lines derived from endocrine/solid tumors. Specifically, IHC, immunofluorescence, western blot and RT-PCR assay results have demonstrated that PI3Kδ isoforms were highly expressed in endocrine/solid tumor patient specimens and cell lines.ResultsDifferential PIK3CD-S/PIK3CD-L expression profiles were identified in a panel of endocrine/solid tumor cells. SiRNA knockdown of PIK3CD-L or PIK3CD-S differentially inhibits AKT/mTOR signaling in PCa, breast, colon and lung cancer cell lines. Moreover, siRNA knockdown of PTEN increased PI3Kδ levels and activated AKT/mTOR signaling, while overexpression of PTEN reduced PI3Kδ levels and inhibited AKT/mTOR signaling in cancer cells. Intriguingly, PI3Kδ-S levels remained unchanged upon either siRNA knockdown or overexpression of PTEN. Taken together, these results suggested that PTEN negatively regulates PI3Kδ-L and its downstream AKT/mTOR signaling, while PI3Kδ-S promotes AKT/mTOR signaling without regulation by PTEN. Lastly, PI3Kδ inhibitor Idelalisib and SRPK1/2 inhibitor SRPIN340 were employed to assess their efficacies on inhibiting the PI3Kδ-expressing endocrine/solid tumors. Our results have shown that Idelalisib effectively inhibited PI3Kδ-L (but not PI3Kδ-S) mediated AKT/mTOR signaling. In contrast, SRPIN340 reversed the aberrant mRNA splicing, thereby inhibiting AKT/mTOR signaling. In-vitro functional assays have further demonstrated that a combination of Idelalisib and SRPIN340 achieved a synergistic drug effect (with drastically reduced cell viabilities/growths of tumor spheroids) in inhibiting the advanced tumor cells.ConclusionIn summary, our study has suggested a promising potential of utilizing PI3Kδ-S (an oncogenic isoform conferring drug resistance and exempt from PTEN regulation) as a prognostic biomarker and drug target in advanced endocrine cancers.

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The (pro)renin receptor: a novel biomarker and potential therapeutic target for various cancers.

Publications

The (pro)renin receptor: a novel biomarker and potential therapeutic target for various cancers.

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