Medical Hypotheses 80 (2013) 672–674

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Medical Hypotheses

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Androgen receptor may be responsible for gender disparity in gastric cancer

Ye Tian a, Han Wan a, Yao Lin a, Xu Xie a, ZeYu Li b, Guang Tan a,⇑a Department of General Surgery, First Affiliated Hospital, Dalian Medical University, PR Chinab Department of Urology, First Affiliated Hospital, Jilin University, PR China

a r t i c l e i n f o a b s t r a c t

Article history:Received 20 November 2012Accepted 18 January 2013

0306-9877/$ - see front matter � 2013 Elsevier Ltd. Ahttp://dx.doi.org/10.1016/j.mehy.2013.01.023

⇑ Corresponding author. Address: 222 Zhong ShanPR China. Tel.: +86 13941122439.

E-mail address: lityetian@yahoo.com.cn (G. Tan).

Men are at a higher risk of developing gastric cancer than women. However, the exact mechanismsresponsible for the gender differences remain unclear. Recently, a number of epidemiological and geno-typing studies have attributed the gender disparity in male-predominant cancers to the disruption ofandrogen receptor (AR) homeostasis. Moreover, previous data indicated that AR expression is an indepen-dent unfavorable prognostic factor in gastric cancer, suggesting that AR may play an important role ingastric carcinogenesis. In addition, mounting evidence suggests that AR is involved in many signalingpathways associated with gastric carcinogenesis. On the basis of the aforementioned evidence, we pos-tulate that AR exhibits oncogenic properties in gastric cancer via several possible mechanisms, whichmay partly explain the higher prevalence of gastric cancer among males.

� 2013 Elsevier Ltd. All rights reserved.

Introduction

Gastric cancer is the fourth most common cancer worldwide,and it is more common in developing countries [1]. Epidemiologi-cal reports indicate that regardless of etiologies, the incidence ofgastric cancer is higher in males than in females with a male-to-fe-male ratio of approximately 2:1 [2]. Elucidating the factors causingthe sex-related disparity of gastric cancer may be considered as akey for unrevealing critical pathways in gastric carcinogenesis.However, very limited information is currently available regardingthe mechanism of this remarkable gender disparity. Here we pos-tulate a hypothesis that androgen receptor (AR) may be responsi-ble for this sex-related disparity.

Androgen receptor in carcinogenesis

The AR, also known as NR3C4 (nuclear receptor subfamily 3,group C, member 4), belong to the family of nuclear receptors thatact as transcription factors and regulate the expression of severalgenes [3]. Many studies have described the functions of AR in bothandrogen-dependent and androgen-independent manners [4–6].The expression and functional status of AR has been correlatedwith the process of carcinogenesis of all reproductive organs. How-ever, recent evidence reveals that AR appears to play a significantrole in the carcinogenesis of various organs other than reproduc-tive organs [7–9]. Overexpression of AR has been demonstratedin a number of human malignancies [5,8,10]. Various in vitro as

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Lu, Dalian, Liaoning 116011,

well as vivo studies have provided data suggesting that the overex-pression of AR promotes tumorigenicity [7,11,12]. Moreover, ARhas been shown to play a dominant role in determining the genderspecificity of several human tumors [5,13,14]. Especially, Yeh andChen reported that AR had stimulatory effects on hepatocellularcarcinoma (HCC), which may explain the gender disparity of HCC[15]. Furthermore, in gastric cancer, the higher AR expression isassociated with lymph node metastases and poor prognosis [16].

Hypothesis. Androgen receptor may play a critical role in gastriccarcinogenesis and be responsible for gender-specific difference inthe incidence

The hypothesis is based on the following evidences.

(1) In 1990, Wu and colleagues demonstrated the presence of ARin gastric cancer tissues [17]. Since then, several reportsshowing expression of AR in the stomach have been pub-lished [18–20]. The significance of the AR in the prognosisof gastric cancer has been studied. It was reported that ARnegative patients show significantly better survival than ARpositive patients [16]. These results suggest that AR positivestatus in gastric cancer may facilitate cancer invasiveness.

(2) Male-predominant cancers refer to human malignancieswhich have higher incidence in males. HCC, bladder cancer,gastric cancer and pancreatic cancer belong to male-pre-dominant cancers. In view of this remarkable gender dispar-ity, a number of studies have tried to explore the importanceof androgen axis in these cancers [3,12,14,21,22]. The resultsdemonstrated that the aberrant expression or function of ARis the major contributor to the sex-related disparity in blad-der cancer, HCC and pancreatic cancer, indicating the strong

Y. Tian et al. / Medical Hypotheses 80 (2013) 672–674 673

oncogenic properties of AR in these tumors [5,7,15]. Consid-ering that gastric cancer also belongs to male-predominantcancers, similar mechanisms of AR regulation may contrib-ute to gastric carcinogenesis.

(3) An increasing body of evidence from in vitro and in vivostudies has shown that AR not only mediates the effects ofandrogen but also function as an oncoprotein by interactingwith other molecules implicated in the regulation of cellproliferation, tumor growth and/or metastasis in gastric car-cinogenesis [7,12,23,24]. Moreover, it has been shown thatAR is functionally connected to a broad range of oncogenicsignaling pathways, especially those crucially relevant forgastric tumorigenesis including the Wnt and EGF/EGFR sig-naling pathways [7,12]. These data raise the possibility thatAR may function as a novel oncoprotein to promote the ini-tiation and progression of gastric cancer.

The mechanisms by which AR contributes to gastriccarcinogenesis

Based on current literature, we postulate several mechanims bywhich AR contributes to gastric carcinogenesis (Table 1).

AR disrupts the biological function of the tumor suppressor proteins

The tumor suppressor proteins restrain cell growth or prolifer-ation, and prevent malignant transformation. Suppression of tumorsuppressor protein p53 has been demonstrated in 60% of humangastric cancers [27]. Abnormal expression of p53 has been impli-cated in the process of carcinogenesis. Apart from its well-docu-mented cytostatic effects, p53 modulates AR activity viaregulating the specificity of chromatin binding by AR [28]. More-over, Ma et al. show that AR could disrupt p53-mediated DNAdamage sensing/repairing system, thereby promote hepatocarcino-genesis [4]. We presume that the interaction between AR and p53may lead to the suppression of p53 and the increased expression ofAR. Consequently, growth-inhibiting ability of p53 is inhibited andtumor-promoting effects of AR are augmented, leading to gastriccarcinogenesis.

Molecules that normally inhibit the entry into the cell cycle,such as p27, show diminished expression in nearly one half of gas-tric cancers [29,30]. p27 could bind cyclin E-CDK2 or cyclin D-CDK4 complexes and prevent their activation, thus controllingthe cell cycle progression at G1 [31]. Absence of p27 expressionis associated with poor prognosis of gastric cancer [29]. Intrigu-ingly, AR degrades p27 late in the G1 phase in a ubiquitin-protea-some-dependent manner [24]. These data are in agreement withthe fact that high expression levels of AR are associated with lowexpression levels of p27 and poor prognosis in prostate cancer[24]. It is thus tempting to propose that down-regulation of p27in gastric carcinogenesis is partially mediated by AR.

Furthermore, it is well-known that diminished expression ofE-cadherin is common in gastric cancer (in 51% of cases) and asso-ciated with higher rates of lymph node metastases and reducedsurvival [32]. In vitro studies suggest that decreased expressionof E-cadherin promotes the dissociation of cancer cells from the

Table 1The potential role of AR signals on the expression/activity of key molecules

Molecules Main function

P53 Cell cycle regulation, apoptosisP27 Cell cycle regulationE-cadherin Cell migration and invasionb-catenin Cell growth and adhesionEGFR Cell proliferation, migration and invasion

extracellular matrix, enhancing the migration and invasion of gas-tric cancer cells [32,33]. Interestingly, a recent elegant study indi-cated that AR promotes the activation of epithelial-mesenchymaltransition and tumor metastasis by downregulating E-cadherinexpression [25]. Therefore, it is conceivable to presume that theabnormal low expression of E-cadherin in gastric cancer mightbe, at least in part, caused by AR.

AR auguments the expression/activity of oncoproteins

In addition to the role in the inhibition of various tumor sup-pressor proteins, AR may promote gastric carcinogenesis via up-regulating the expression/activity of oncoproteins.

The oncogenic b-catenin is frequently activated in human gastriccancer [34]. b-Catenin is a subunit of the cadherin protein complexand has been suggested as the most important mediator in the Wntsignaling pathway [35,36]. Upon activation, b-catenin is subse-quently translocated into the nucleus, where it binds the Tcell fac-tor (TCF)/LEF family of transcription factors to regulate target geneexpression and cell proliferation. Feng et al. reported that AR pro-vokes tumor-associated cell cycle defects to induce unscheduledproliferation through the activation of b-catenin signaling in HCC[7]. In addition, Wnt3a could recruit AR to the promoter regionsof Myc and Cyclin D1, which are well-characterized downstreamtargets of the Wnt signalling pathway. AR and b-Catenin couldinteract directly and AR promotes Wnt signaling at the chromatinlevel [37]. On the other hand, Wnt3a induced AR-mediated tran-scription and enhanced the growth of human prostate cancer cells[38]. Considering the resemblance between HCC and gastric cancerin their epidemiology and aberrant activation of the Wnt signalingpathway in HCC, prostate cancer and gastric cancer, we proposethat AR may play a critical role in gastric carcinogenesis throughupregulating Wnt/b-catenin signaling.

Approximately 15% of gastric cancers have been reported tooverexpress both epidermal growth factor (EGF) and EGF receptor(EGFR). Interestingly, the ligand-activated AR has been shown todirectly up-regulate the expression of EGFR as well as the levelsof phosphorylation of the downstream protein AKT, and EGF in-duces bladder cancer cell proliferation through the activation ofAR [5,12,26]. These findings raise the possibility that cross-talk be-tween AR and EGFR pathways plays an important role in gastriccancer progression.

Conclusion and perspective

To summarize, we postulate that AR plays a central role in gas-tric carcinogenesis through the modulation of the expression or/and the activity of both oncoproteins and tumor suppresser pro-teins (Table 1).The potential oncogenic properties of AR might con-tribute to the gender difference of gastric cancer incidence.However, it is worth noting that the different risk factors such asdrinking, smoking and helicobacter pylori infection are also theimportant reasons responsibe for the gender difference of gastriccancer.

related to gastric cancer cell growth.

AR effect References

Down-regulation [4]Down-regulation [24]Down-regulation [25]Up-regulation [7]Up-regulation [26]

674 Y. Tian et al. / Medical Hypotheses 80 (2013) 672–674

Next, we can take the following steps to test our hypothesis. (1)A thorough re-examination of previous studies using specific, sen-sitive and quantitative methods to detect the expression of AR innormal and neoplastic gastric tissues. (2) Further expression-pro-filing studies to determine possible relationships between ARmRNA or protein levels and various clinicopathological and prog-nostic parameters in different grades of cancer patient samples.(3) RNA interference and transfection studies to further explorethe function of AR in gastric cancer. (4) AR knockdown approachto examine the consequences on the expression and activity ofoncoproteins important for cell cycle regulation.

The ultimate aim of the testable hypotheses is to translate theminto clinical applications. If the role of AR as an important regulatorin gastric tumorigenicity is confirmed, AR may serve as a novelprognostic cancer marker and a new target of gastric cancertherapeutics.

Conflict of interest statement

None.

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