scholarly journals PMEPA1 Gene Isoforms: A Potential Biomarker and Therapeutic Target in Prostate Cancer

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1221
Author(s):  
Shashwat Sharad ◽  
Albert Dobi ◽  
Shiv Srivastava ◽  
Alagarsamy Srinivasan ◽  
Hua Li
Keyword(s):  
Prostate Cancer ◽  
Solid Tumors ◽  
Cancer Progression ◽  
Therapeutic Target ◽  
Gene Networks ◽  
Transmembrane Protein ◽  
Regulatory Gene ◽  
Amino Acid Sequences ◽  
Binding Domains ◽  
Potential Biomarker

The identification of prostate transmembrane protein androgen induced 1 (PMEPA1), an androgen responsive gene, came initially from the studies of androgen regulatory gene networks in prostate cancer. It was soon followed by the documentation of the expression and functional analysis of transmembrane prostate androgen-induced protein (TMEPAI)/PMEPA1 in other solid tumors including renal, colon, breast, lung, and ovarian cancers. Further elucidation of PMEPA1 gene expression and sequence analysis revealed the presence of five isoforms with distinct extracellular domains (isoforms a, b, c, d, and e). Notably, the predicted amino acid sequences of PMEPA1 isoforms show differences at the N-termini, a conserved membrane spanning and cytoplasmic domains. PMEPA1 serves as an essential regulator of multiple signaling pathways including androgen and TGF-β signaling in solid tumors. Structure-function studies indicate that specific motifs present in the cytoplasmic domain (PY, SIM, SH3, and WW binding domains) are utilized to mediate isoform-specific functions through interactions with other proteins. The understanding of the “division of labor” paradigm exhibited by PMEPA1 isoforms further expands our knowledge of gene’s multiple functions in tumorigenesis. In this review, we aim to summarize the most recent advances in understanding of PMEPA1 isoform-specific functions and their associations with prostate cancer progression, highlighting the potentials as biomarker and therapeutic target in prostate cancer.

scholarly journals TMEFF2: A Transmembrane Proteoglycan with Multifaceted Actions in Cancer and Disease

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3862
Author(s):  
Motasim Masood ◽  
Stefan Grimm ◽  
Mona El-Bahrawy ◽  
Ernesto Yagüe
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Transmembrane Protein ◽  
Intracellular Localization ◽  
Amyloid Β ◽  
Inverse Correlation ◽  
Response To Therapy ◽  
Endocrine Function ◽  
Type I ◽  
Amyloid Β Protein

Transmembrane protein with an EGF-like and two Follistatin-like domains 2 (TMEFF2) is a 374-residue long type-I transmembrane proteoglycan which is proteolytically shed from the cell surface. The protein is involved in a range of functions including metabolism, neuroprotection, apoptosis, embryonic development, onco-suppression and endocrine function. TMEFF2 is methylated in numerous cancers, and an inverse correlation with the stage, response to therapy and survival outcome has been observed. Moreover, TMEFF2 methylation increases with breast, colon and gastric cancer progression. TMEFF2 is methylated early during oncogenesis in breast and colorectal cancer, and the detection of methylated free-circulating TMEFF2 DNA has been suggested as a potential diagnostic tool. The TMEFF2 downregulation signature equals and sometimes outperforms the Gleason and pathological scores in prostate cancer. TMEFF2 is downregulated in glioma and cotricotropinomas, and it impairs the production of adrenocorticotropic hormone in glioma cells. Interestingly, through binding the amyloid β protein, its precursor and derivatives, TMEFF2 provides neuroprotection in Alzheimer’s disease. Despite undergoing extensive investigation over the last two decades, the primary literature regarding TMEFF2 is incoherent and offers conflicting information, in particular, the oncogenic vs. onco-suppressive role of TMEFF2 in prostate cancer. For the first time, we have compiled, contextualised and critically analysed the vast body of TMEFF2-related literature and answered the apparent discrepancies regarding its function, tissue expression, intracellular localization and oncogenic vs. onco-suppressive role.

scholarly journals Identification of a novel Protein Disulfide-isomerase A3 (PDIA3) transcript variant as a potential biomarker associated with late stage prostate cancer

2019 ◽  
Author(s):  
Maria Araceli Diaz Cruz ◽  
Pontus Karlsson ◽  
Gustav Högberg ◽  
Sandra Karlsson ◽  
Ferenc Szekeres ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Vitamin D ◽  
Cancer Progression ◽  
Vitamin D Receptor ◽  
Digital Pcr ◽  
Droplet Digital Pcr ◽  
Receptor Protein ◽  
Lncap Cells ◽  
Transcript Isoforms ◽  
Potential Biomarker

Abstract Background Prostate cancer (PC) is a heterogeneous and unpredictable disease and becomes untreatable when the tumor progress to castrate-resistant (CR) or androgen independent (AI). A major clinical challenge in prostate cancer is the lack of diagnostic and prognostic tests that distinguish between benign and aggressive tumors. Isoforms of gene transcripts are emerging as suitable candidates to represent disease progression. Vitamin D receptor (VDR and PDIA3) transcript isoforms could be the target candidates of study since they have been related with anti-tumoral effects and carcinogenesis in several cancer types. Methods The current study investigates the role of vitamin D receptor transcript isoforms in prostate cancer progression by using Next Generation Sequencing (NGS), Droplet Digital PCR (ddPCR) and several functional prediction tools. Results The NGS analysis revealed a novel PDIA3 transcript isoform (PDIA3N) that is higher expressed than the PDIA3 isoform that codifies for the receptor protein, in prostate cells. The expression of PDIA3N was validated by droplet digital PCR (ddPCR) absolute quantification, which confirmed the findings from the NGS analyses. The PDIA3N isoform was present in higher levels than PDIA3, in the metastatic androgen dependent LNCaP cells. Furthermore, analysis of the novel PDIA3 isoform sequence indicate that the variations present in its sequence are altering the original protein function and structure as well as the predicted subcellular localization of the protein. Conclusions We conclude that, PDIA3N due to the high expression in LNCaP cells and its abnormality in predicted structure, localization and function, is a potential biomarker for prostate cancer disease that needs to be further investigated in prostate cancer samples.

scholarly journals Curcumin-Gene Expression Response in Hormone Dependent and Independent Metastatic Prostate Cancer Cells

2019 ◽  
Vol 20 (19) ◽  
pp. 4891 ◽  
Author(s):  
Shilpa Katta ◽  
Arun Srivastava ◽  
Rajesh L. Thangapazham ◽  
Inger L. Rosner ◽  
Jennifer Cullen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Gene Networks ◽  
Transforming Growth Factor ◽  
Transmembrane Protein ◽  
Bhlh Transcription Factor ◽  
Prostate Cancer Cells ◽  
Curcumin Treatment ◽  
Gene Expression Response

The androgen receptor is one of the key targets for prostate cancer treatment. Despite its less satisfactory effects, chemotherapy is the most common treatment option for metastatic and/or castration-resistant patients. There are constant needs for novel anti-prostate cancer therapeutic/prevention agents. Curcumin, a known chemo-preventive agent, was shown to inhibit prostate cancer cell growth. This study aimed to unravel the inhibitory effect of curcumin in prostate cancer through analyzing the alterations of expressions of curcumin targeting genes clusters in androgen-dependent LNCaP cells and androgen-independent metastatic C4-2B cells. Hierarchical clustering showed the highest number of differentially expressed genes at 12 h post treatment in both cells, suggesting that the androgen-dependent/independent manner of curcumin impacts on prostate cancer cells. Evaluation of significantly regulated top canonical pathways highlighted that Transforming growth factor beta (TGF-β), Wingless-related integration site (Wnt), Phosphoinositide 3-kinase/Protein Kinase B/ mammalian target of rapamycin (PIK3/AKT(PKB)/mTOR), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling were primarily inhibited, and Phosphatase and tensin homolog (PTEN) dependent cell cycle arrest and apoptosis pathways were elevated with curcumin treatment. The short term (3–24 h) and long term (48 h) effect of curcumin treatment revealed 31 and four genes modulated in both cell lines. TGF-β signaling, including the androgen/TGF-β inhibitor Prostate transmembrane protein androgen-induced 1 (PMEPA1), was the only pathway impacted by curcumin treatment after 48 h. Our findings also established that MYC Proto-Oncogene, basic helix-loop-helix (bHLH) Transcription Factor (MYC) signaling was down-regulated in curcumin-treated cell lines. This study established, for the first time, novel gene-networks and signaling pathways confirming the chemo-preventive and cancer-growth inhibitory nature of curcumin as a natural anti-prostate cancer compound.

scholarly journals Role and Involvement of TENM4 and miR-708 in Breast Cancer Development and Therapy

Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 172
Author(s):  
Giulia Peppino ◽  
Federica Riccardo ◽  
Maddalena Arigoni ◽  
Elisabetta Bolli ◽  
Giuseppina Barutello ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Nervous System ◽  
Cancer Progression ◽  
System Development ◽  
Transmembrane Protein ◽  
Nervous System Development ◽  
Potential Biomarker ◽  
Report Data ◽  
Novel Target ◽  
Patient Prognosis

Teneurin 4 (TENM4) is a transmembrane protein that is codified by the ODZ4 gene and is involved in nervous system development, neurite outgrowth, and neuronal differentiation. In line with its involvement in the nervous system, TENM4 has also been implicated in several mental disorders such as bipolar disorder, schizophrenia, and autism. TENM4 mutations and rearrangements have recently been identified in a number of tumors. This, combined with impaired expression in tumors, suggests that it may potentially be involved in tumorigenesis. Most of the TENM4 mutations that are observed in tumors occur in breast cancer, in which TENM4 plays a role in cells’ migration and stemness. However, the functional role that TENM4 plays in breast cancer still needs to be better evaluated, and further studies are required to better understand the involvement of TENM4 in breast cancer progression. Herein, we review the currently available data for TENM4′s role in breast cancer and propose its use as both a novel target with which to ameliorate patient prognosis and as a potential biomarker. Moreover, we also report data on the tumorigenic role of miR-708 deregulation and the possible use of this miRNA as a novel therapeutic molecule, as miR-708 is spliced out from TENM4 mRNA.

scholarly journals Identification of transcription factor co-regulators that drive prostate cancer progression

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Manjunath Siddappa ◽  
Sajad A. Wani ◽  
Mark D. Long ◽  
Damien A. Leach ◽  
Ewy A. Mathé ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transcription Factor ◽  
Cancer Progression ◽  
Cell Biology ◽  
Gene Networks ◽  
Disease Free Survival ◽  
Rna Seq ◽  
Free Survival ◽  
Altered Gene ◽  
Disease Free

AbstractIn prostate cancer (PCa), and many other hormone-dependent cancers, there is clear evidence for distorted transcriptional control as disease driver mechanisms. Defining which transcription factor (TF) and coregulators are altered and combine to become oncogenic drivers remains a challenge, in part because of the multitude of TFs and coregulators and the diverse genomic space on which they function. The current study was undertaken to identify which TFs and coregulators are commonly altered in PCa. We generated unique lists of TFs (n = 2662), coactivators (COA; n = 766); corepressors (COR; n = 599); mixed function coregulators (MIXED; n = 511), and to address the challenge of defining how these genes are altered we tested how expression, copy number alterations and mutation status varied across seven prostate cancer (PCa) cohorts (three of localized and four advanced disease). Testing of significant changes was undertaken by bootstrapping approaches and the most significant changes were identified. For one commonly and significantly altered gene were stably knocked-down expression and undertook cell biology experiments and RNA-Seq to identify differentially altered gene networks and their association with PCa progression risks. COAS, CORS, MIXED and TFs all displayed significant down-regulated expression (q.value < 0.1) and correlated with protein expression (r 0.4–0.55). In localized PCa, stringent expression filtering identified commonly altered TFs and coregulator genes, including well-established (e.g. ERG) and underexplored (e.g. PPARGC1A, encodes PGC1α). Reduced PPARGC1A expression significantly associated with worse disease-free survival in two cohorts of localized PCa. Stable PGC1α knockdown in LNCaP cells increased growth rates and invasiveness and RNA-Seq revealed a profound basal impact on gene expression (~ 2300 genes; FDR < 0.05, logFC > 1.5), but only modestly impacted PPARγ responses. GSEA analyses of the PGC1α transcriptome revealed that it significantly altered the AR-dependent transcriptome, and was enriched for epigenetic modifiers. PGC1α-dependent genes were overlapped with PGC1α-ChIP-Seq genes and significantly associated in TCGA with higher grade tumors and worse disease-free survival. These methods and data demonstrate an approach to identify cancer-driver coregulators in cancer, and that PGC1α expression is clinically significant yet underexplored coregulator in aggressive early stage PCa.

Increased fatty acid synthase as a therapeutic target in androgen-independent prostate cancer progression

The Prostate ◽  
2001 ◽  
Vol 47 (2) ◽  
pp. 102-110 ◽  
Author(s):  
Ellen S. Pizer ◽  
Beth R. Pflug ◽  
G. Steven Bova ◽  
Wan Fang Han ◽  
Michael S. Udan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Fatty Acid ◽  
Cancer Progression ◽  
Therapeutic Target ◽  
Fatty Acid Synthase ◽  
Prostate Cancer Progression ◽  
Androgen Independent

scholarly journals Expression and Subcellular Localization of Discoidin Domain Receptor 1 (DDR1) Define Prostate Cancer Aggressiveness

2021 ◽  
Author(s):  
R. Daniel Bonfil ◽  
Wei Chen ◽  
Semir Vranic ◽  
Anjum Sohail ◽  
Dongping Shi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Subcellular Localization ◽  
Cancer Progression ◽  
Normal Tissue ◽  
Multivariate Logistic Regression Model ◽  
Normal Prostate ◽  
Discoidin Domain Receptor ◽  
Potential Biomarker ◽  
Cancer Aggressiveness ◽  
Discoidin Domain Receptor 1

Abstract Background: The Discoidin Domain Receptor 1 (DDR1) is one of the two members of a unique family of receptor tyrosine kinase receptors that signal in response to collagen, which has been implicated in cancer progression. Here, we examined the expression of DDR1 in prostate cancer (PCa), and assessed its potential value as a prognostic marker, as a function of grade, stage and other clinicopathologic parameters.Methods: We investigated the association between the expression level and subcellular localization of DDR1 protein and PCa aggressiveness by immunohistochemistry, using tissue microarrays (TMAs) encompassing 200 cases of PCa with various Gleason scores (GS) and pathologic stages with matched normal tissue, and a highly specific monoclonal antibody. Results: DDR1 was found to be localized in the membrane, cytoplasm, and nuclear compartments of both normal and cancerous prostate epithelial cells. Analyses of DDR1 expression in low GS (≤7[3+4]) vs high GS (≥7[4+3]) tissues showed no differences in nuclear or cytoplasmic DDR1in either cancerous or adjacent normal tissue cores. However, relative to normal-matched tissue, the percentage of cases with higher membranous DDR1 expression was significantly lower in high vs. low GS cancers. Although nuclear localization of DDR1 was consistently detected in our tissue samples and also in cultured human PCa and normal prostate-derived cell lines, its presence in that site could not be associated with disease aggressiveness. No associations between DDR1 expression and overall survival or biochemical recurrence were found in this cohort of patients. Conclusion: The data obtained through multivariate logistic regression model analysis suggest that the level of membranous DDR1 expression status may represent a potential biomarker of utility for better determination of PCa aggressiveness.

scholarly journals PMEPA1 Is a Prognostic Biomarker That Correlates With Cell Malignancy and the Tumor Microenvironment in Bladder Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Dongxu Qiu ◽  
Jian Hu ◽  
Jiao Hu ◽  
Anze Yu ◽  
Belaydi Othmane ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Molecular Subtype ◽  
Transmembrane Protein ◽  
Treatment Options ◽  
Potential Biomarker ◽  
Cell Malignancy

Prostate transmembrane protein androgen induced 1 (PMEPA1) has been reported to promote cancer progression, but the potential role of PMEPA1 in bladder cancer (BLCA) remains elusive. We assess the role of PMEPA1 in BLCA, via a publicly available database and in vitro study. PMEPA1 was identified from 107 differentially expressed genes (DEGs) to have prognostic value. GO, KEGG, and GSEA analysis indicated that PMEPA1 was involved in cancer progression and the tumor microenvironment (TME). Then bioinformatical analysis in TCGA, GEO, TIMER, and TISIDB show a positive correlation with the inflammation and infiltration levels of three tumor-infiltrating immune cells (TAMs, CAFs, and MDSCs) and immune/stromal scores in TME. Moreover, in vitro study revealed that PMEPA1 promotes bladder cancer cell malignancy. Immunohistochemistry and survival analysis shed light on PMEPA1 potential to be a novel biomarker in predicting tumor progression and prognosis. At last, we also analyzed the role of PMEPA1 in predicting the molecular subtype and the response to several treatment options in BLCA. We found that PMEPA1 may be a novel potential biomarker to predict the progression, prognosis, and molecular subtype of BLCA.

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