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   Table of Contents - Current issue
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May-June 2019
Volume 21 | Issue 3
Page Nos. 213-318

Online since Tuesday, April 23, 2019

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INVITED EDITORIAL  

Prostate cancer: molecular and cellular mechanisms and their implications in therapy resistance and disease progression p. 213
Ninghan Feng, Jiaoti Huang
DOI:10.4103/aja.aja_31_19  PMID:30971530
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INVITED REVIEW Top

Transcriptional repression by androgen receptor: roles in castration-resistant prostate cancer p. 215
Galina Gritsina, Wei-Qiang Gao, Jindan Yu
DOI:10.4103/aja.aja_19_19  PMID:30950412
Androgen receptor (AR), a hormonal transcription factor, plays important roles during prostate cancer progression and is a key target for therapeutic interventions. While androgen-deprivation therapies are initially successful in regressing prostate tumors, the disease ultimately comes back as castration-resistant prostate cancer (CRPC) or at the late stage as neuroendocrine prostate cancer (NEPC). CRPC remains largely dependent on hyperactive AR signaling in the milieu of low androgen, while NEPC is negative of AR expression but positive of many AR-repressed genes. Recent technological advances in genome-wide analysis of transcription factor binding sites have revealed an unprecedented set of AR target genes. In addition to its well-known function in activating gene expression, AR is increasingly known to also act as a transcriptional repressor. Here, we review the molecular mechanisms by which AR represses gene expression. We also summarize AR-repressed genes that are aberrantly upregulated in CRPC and NEPC and represent promising targets for therapeutic intervention.
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B lymphoma Moloney murine leukemia virus insertion region 1: An oncogenic mediator in prostate cancer Highly accessed article p. 224
Qipeng Liu, Qiaqia Li, Sen Zhu, Yang Yi, Qi Cao
DOI:10.4103/aja.aja_38_18  PMID:29862993
B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1), a core member of polycomb repressive complex 1 (PRC1), has been intensely investigated in the field of cancer epigenetics for decades. Widely known as a critical regulator in cellular physiology, BMI1 is essential in self-renewal and differentiation in different lineages of stem cells. BMI1 also plays a significant role in cancer etiology for its involvement in pathological progress such as epithelial–mesenchymal transition (EMT) and cancer stem cell maintenance, propagation, and differentiation. Importantly, overexpression of BMI1 is predictive for drug resistance, tumor recurrence, and eventual therapy failure of various cancer subtypes, which renders the pharmacological targeting at BMI1 as a novel and promising therapeutic approach. The study on prostate cancer, a prevalent hormone-related cancer among men, has promoted enormous research advancements in cancer genetics and epigenetics. This review summarizes the role of BMI1 as an oncogenic and epigenetic regulator in tumor initiation, progression, and relapse of prostate cancer.
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The regulatory pathways leading to stem-like cells underlie prostate cancer progression p. 233
Chun-Jung Lin, U-Ging Lo, Jer-Tsong Hsieh
DOI:10.4103/aja.aja_72_18  PMID:30178777
Prostate cancer (PCa) is the most common cause of malignancy in males and the third leading cause of cancer mortality in the United States. The standard care for primary PCa with local invasive disease mainly is surgery and radiation. For patients with distant metastases, androgen deprivation therapy (ADT) is a gold standard. Regardless of a favorable outcome of ADT, patients inevitably relapse to an end-stage castration-resistant prostate cancer (CRPC) leading to mortality. Therefore, revealing the mechanism and identifying cellular components driving aggressive PCa is critical for prognosis and therapeutic intervention. Cancer stem cell (CSC) phenotypes characterized as poor differentiation, cancer initiation with self-renewal capabilities, and therapeutic resistance are proposed to contribute to the onset of CRPC. In this review, we discuss the role of CSC in CRPC with the evidence of CSC phenotypes and the possible underlying mechanisms.
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Lineage plasticity-mediated therapy resistance in prostate cancer Highly accessed article p. 241
Alexandra M Blee, Haojie Huang
DOI:10.4103/aja.aja_41_18  PMID:29900883
Therapy resistance is a significant challenge for prostate cancer treatment in clinic. Although targeted therapies such as androgen deprivation and androgen receptor (AR) inhibition are effective initially, tumor cells eventually evade these strategies through multiple mechanisms. Lineage reprogramming in response to hormone therapy represents a key mechanism that is increasingly observed. The studies in this area have revealed specific combinations of alterations present in adenocarcinomas that provide cells with the ability to transdifferentiate and perpetuate AR-independent tumor growth after androgen-based therapies. Interestingly, several master regulators have been identified that drive plasticity, some of which also play key roles during development and differentiation of the cell lineages in the normal prostate. Thus, further study of each AR-independent tumor type and understanding underlying mechanisms are warranted to develop combinational therapies that combat lineage plasticity in prostate cancer.
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Impact of taxanes on androgen receptor signaling Highly accessed article p. 249
Shanshan Bai, Bryan Y Zhang, Yan Dong
DOI:10.4103/aja.aja_37_18  PMID:29900882
The development and progression of metastatic castration-resistant prostate cancer is the major challenge in the treatment of advanced prostate cancer. The androgen receptor signaling pathway remains active in metastatic castration-resistant prostate cancer. Docetaxel and cabazitaxel are the first- and second-line chemotherapy, respectively, for patients with metastatic castration-resistant prostate cancer. These two taxanes, in general, function by (i) inhibiting mitosis and inducing apoptosis and (ii) preventing microtubule-dependent cargo trafficking. In prostate cancer, taxanes have been reported to inhibit the nuclear translocation and activity of the androgen receptor. However, whether this is attainable or not clinically remains controversial. In this review, we will provide a comprehensive view of the effects of taxanes on androgen receptor signaling in prostate cancer.
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Beta-adrenergic signaling on neuroendocrine differentiation, angiogenesis, and metastasis in prostate cancer progression Highly accessed article p. 253
Yicheng Zhao, Wenliang Li
DOI:10.4103/aja.aja_32_18  PMID:29848834
Prostate cancer is a complex, heterogeneous disease that mainly affects the older male population with a high-mortality rate. The mechanisms underlying prostate cancer progression are still incompletely understood. Beta-adrenergic signaling has been shown to regulate multiple cellular processes as a mediator of chronic stress. Recently, beta-adrenergic signaling has been reported to affect the development of aggressive prostate cancer by regulating neuroendocrine differentiation, angiogenesis, and metastasis. Here, we briefly summarize and discuss recent advances in these areas and their implications in prostate cancer therapeutics. We aim to provide a better understanding of the contribution of beta-adrenergic signaling to the progression of aggressive prostate cancer.
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Battle of the sexes: contrasting roles of testis-specific protein Y-encoded (TSPY) and TSPX in human oncogenesis p. 260
Yun-Fai Chris Lau, Yunmin Li, Tatsuo Kido
DOI:10.4103/aja.aja_43_18  PMID:29974883
The Y-located testis-specific protein Y-encoded (TSPY) and its X-homologue TSPX originated from the same ancestral gene, but act as a proto-oncogene and a tumor suppressor gene, respectively. TSPY has specialized in male-specific functions, while TSPX has assumed the functions of the ancestral gene. Both TSPY and TSPX harbor a conserved SET/NAP domain, but are divergent at flanking structures. Specifically, TSPX contains a C-terminal acidic domain, absent in TSPY. They possess contrasting properties, in which TSPY and TSPX, respectively, accelerate and arrest cell proliferation, stimulate and inhibit cyclin B-CDK1 phosphorylation activities, have no effect and promote proteosomal degradation of the viral HBx oncoprotein, and exacerbate and repress androgen receptor (AR) and constitutively active AR variant, such as AR-V7, gene transactivation. The inhibitory domain has been mapped to the carboxyl acidic domain in TSPX, truncation of which results in an abbreviated TSPX exerting positive actions as TSPY. Transposition of the acidic domain to the C-terminus of TSPY results in an inhibitory protein as intact TSPX. Hence, genomic mutations/aberrant splicing events could generate TSPX proteins with truncated acidic domain and oncogenic properties as those for TSPY. Further, TSPY is upregulated by AR and AR-V7 in ligand-dependent and ligand-independent manners, respectively, suggesting the existence of a positive feedback loop between a Y-located proto-oncogene and male sex hormone/receptors, thereby amplifying the respective male oncogenic actions in human cancers and diseases. TSPX counteracts such positive feedback loop. Hence, TSPY and TSPX are homologues on the sex chromosomes that function at the two extremes of the human oncogenic spectrum.
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Current opinion and mechanistic interpretation of combination therapy for castration-resistant prostate cancer p. 270
Jin Xu, Yun Qiu
DOI:10.4103/aja.aja_10_19  PMID:30924449
Recent advances in genomics technology have led to the massive discovery of new drug targets for prostate cancer; however, none of the currently available therapeutics is curative. One of the greatest challenges is drug resistance. Combinations of therapies with distinct mechanisms of action represent a promising strategy that has received renewed attention in recent years. Combination therapies exert cancer killing functions through either concomitant targeting of multiple pro-cancer factors or more effective inhibition of a single pathway. Theoretically, the combination therapy can improve efficacy and efficiency compared with monotherapy. Although increasing numbers of drug combinations are currently being tested in clinical trials, the mechanisms by which these combinations can overcome drug resistance have yet to be fully understood. The purpose of this review is to summarize recent work on therapeutic combinations in the treatment of castration-resistant prostate cancer and discuss emerging mechanisms underlying drug resistance. In addition, we provide an overview of the current preclinical mechanistic studies on potential therapeutic combinations to overcome drug resistance.
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Epigenetic regulation of prostate cancer: the theories and the clinical implications p. 279
Yiji Liao, Kexin Xu
DOI:10.4103/aja.aja_53_18  PMID:30084432
Epigenetics is the main mechanism that controls transcription of specific genes with no changes in the underlying DNA sequences. Epigenetic alterations lead to abnormal gene expression patterns that contribute to carcinogenesis and persist throughout disease progression. Because of the reversible nature, epigenetic modifications emerge as promising anticancer drug targets. Several compounds have been developed to reverse the aberrant activities of enzymes involved in epigenetic regulation, and some of them show encouraging results in both preclinical and clinical studies. In this article, we comprehensively review the up-to-date roles of epigenetics in the development and progression of prostate cancer. We especially focus on three epigenetic mechanisms: DNA methylation, histone modifications, and noncoding RNAs. We elaborate on current models/theories that explain the necessity of these epigenetic programs in driving the malignant phenotypes of prostate cancer cells. In particular, we elucidate how certain epigenetic regulators crosstalk with critical biological pathways, such as androgen receptor (AR) signaling, and how the cooperation dynamically controls cancer-oriented transcriptional profiles. Restoration of a “normal” epigenetic landscape holds promise as a cure for prostate cancer, so we concluded by highlighting particular epigenetic modifications as diagnostic and prognostic biomarkers or new therapeutic targets for treatment of the disease.
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Neuroendocrine cells of prostate cancer: biologic functions and molecular mechanisms p. 291
Yu-Hua Huang, Ya-Qun Zhang, Jiao-Ti Huang
DOI:10.4103/aja.aja_128_18  PMID:30924452
Prostate cancer (PCa) is a major health risk for older men worldwide. Existing systemic therapies mostly target androgen receptor (AR). Although treatments are initially effective, the disease always recurs. A potential mechanism for the treatment failure is that PCa contains, in addition to the AR-positive luminal type tumor cells, a small component of neuroendocrine (NE) cells. The function of NE cells in PCa remains poorly understood, and one important characteristic of these cells is their lack of expression of AR and resistance to hormonal therapy. In addition, many patients develop the more aggressive small-cell neuroendocrine carcinoma (SCNC) after hormonal therapy. Although this clinical phenomenon of disease transformation from adenocarcinoma to SCNC is well established, the cell of origin for SCNC remains unclear. Recently, loss of function of Rb and TP53 and amplification and overexpression of MYCN and Aurora A kinase have been identified as important biomarkers and potential disease drivers. In this article, we systematically review the histology of normal prostate and prostate cancer including the main histologic types: adenocarcinoma and SCNC. We also review the findings from many studies using cellular and animal models as well as human specimens that attempt to understand the molecular mechanisms of treatment failure, disease progression, and tumor transformation from adenocarcinoma to SCNC.
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REVIEW Top

Leptin and its actions on reproduction in males p. 296
Ifrah Alam Malik, Damayanthi Durairajanayagam, Harbindar Jeet Singh
DOI:10.4103/aja.aja_98_18  PMID:30539926
Leptin, an adipocyte-derived hormone, serves numerous physiological functions in the body, particularly during puberty and reproduction. The exact mechanism by which leptin activates the gonadotropin-releasing hormone (GnRH) neurons to trigger puberty and reproduction remains unclear. Given the widespread distribution of leptin receptors in the body, both central and peripheral mechanisms involving the hypothalamic-pituitary-gonadal axis have been hypothesized. Leptin is necessary for normal reproductive function, but when present in excess, it can have detrimental effects on the male reproductive system. Human and animal studies point to leptin as a link between infertility and obesity, a suggestion that is corroborated by findings of low sperm count, increased sperm abnormalities, oxidative stress, and increased leptin levels in obese men. In addition, daily leptin administration to normal-weight rats has been shown to result in similar abnormalities in sperm parameters. The major pathways causing these abnormalities remain unidentified; however, these adverse effects have been attributed to leptin-induced increased oxidative stress because they are prevented by concurrently administering melatonin. Studies on leptin and its impact on sperm function are highly relevant in understanding and managing male infertility, particularly in overweight and obese men.
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ORIGINAL ARTICLES Top

Complications of proximal hypospadias repair with transverse preputial island flap urethroplasty: a 15-year experience with long-term follow-up p. 300
Chao-Xu Wang, Wei-Ping Zhang, Hong-Cheng Song
DOI:10.4103/aja.aja_115_18  PMID:30880687
There is still debate regarding the optimal surgical approach for proximal hypospadias. This retrospective study aims to evaluate the long-term outcomes using transverse preputial island flap urethroplasty. A total of 320 patients were included, with a mean follow-up of 40.2 months (range: 1–156 months). Complications were encountered in 125 patients (39.1%), including fistulas in 53 (16.6%), urethral strictures in 31 (9.7%), and diverticula in 41 (12.8%). The mean timing of presentation with a complication was 15.8 months (median: 1.7, range: 1–145), of which 79.2% were early complications and 20.8% were late complications. In all, 20.8% of the patients with complications presented after ≥1 year, and 12.8% presented after ≥5 years. Univariate analysis revealed that age at the time of surgery, flap length, and location of the urethral meatus were not correlated with complications. A stricture was present in 31.7% (13/41) of those with diverticula (P < 0.001), while late urethral diverticula were accompanied by urethral strictures in 11.1% (1/9) of cases (P = 0.213). These results indicate that transverse preputial island flap urethroplasty still has a high incidence of complications, even when performed by highly experienced physicians. Most complications of hypospadias are diagnosed within 1 year postoperatively, while fistulas and urinary strictures generally occur within 2 months and diverticula tend to be present by 1 year.
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Clinical and socioeconomic factors associated with delayed orchidopexy in cryptorchid boys in China: a retrospective study of 2423 cases p. 304
Tian-Xin Zhao, Bin Liu, Yue-Xin Wei, Yi Wei, Xiang-Liang Tang, Lian-Ju Shen, Chun-Lan Long, Tao Lin, Sheng-De Wu, Guang-Hui Wei
DOI:10.4103/aja.aja_106_18  PMID:30632485
We investigated the associations of clinical and socioeconomic factors with delayed orchidopexy for cryptorchidism in China. A retrospective study was conducted on cryptorchid boys who underwent orchidopexy at Children's Hospital at Chongqing Medical University in China from January 2012 to December 2017. Of 2423 patients, 410 (16.9%) received timely repair by 18 months of age, beyond which surgery was considered delayed. Univariate analysis suggested that the laterality of cryptorchidism (P = 0.001), comorbidities including inguinal hernia/scrotal hydrocele (P < 0.001) or urinary tract disease (P = 0.016), and whether patients lived in a poverty county (P < 0.001) could influence whether orchidopexy was timely or delayed. Logistic regression analysis suggested that the following factors were associated with delayed repair: unilateral rather than bilateral cryptorchidism (odds ratio [OR] = 1.752, P < 0.001), absence of inguinal hernia or hydrocele (OR = 2.027, P = 0.019), absence of urinary tract disease (OR = 3.712, P < 0.001), and living in a poverty county (OR = 2.005, P < 0.001). The duration of postoperative hospital stay and hospital costs increased with the patient's age at the time of surgery.
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PLZFposc-KITpos-delineated A1–A4-differentiating spermatogonia by subset and stage detection upon Bouin fixation p. 309
Rui-Ling Tang, Li-Qing Fan
DOI:10.4103/aja.aja_103_18  PMID:30719983
While hallmarks of rodent spermatogonia stem cell biomarkers' heterogeneity have recently been identified, their stage and subset distributions remain unclear. Furthermore, it is currently difficult to accurately identify subset-specific SSC marker distributions due to the poor nuclear morphological characteristics associated with fixation in 4% paraformaldehyde. In the present study, testicular cross-sections and whole-mount samples were Bouin fixed to optimize nuclear resolution and visualized by immunohistochemistry (IHC) and immunofluorescence (IF). The results identified an expression pattern of PLZFhighc-KITpos in A1 spermatogonia, while A2–A4-differentiating spermatogonia were PLZFlowc-KITpos. Additionally, this procedure was used to examine asymmetrically expressing GFRA1 and PLZF clones, asymmetric Apr and false clones were distinguished based on the presence or absence of TEX14, a molecular maker of intercellular bridges, despite having identical nuclear morphology and intercellular distances that were <25 μm. In conclusion, this optimized Bouin fixation procedure facilitates the accurate identification of spermatogonium subsets based on their molecular profiles and is capable of distinguishing asymmetric and false clones. Therefore, the findings presented herein will facilitate further morphological and functional analysis studies and provide further insight into spermatogonium subtypes.
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