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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 30  |  Issue : 5  |  Page : 220-225

The role of c-myc and adiponectin receptors in prostate cancer metastases


1 Department of Urology, Hasan Sadikin Hospital, Universitas Padjadjaran, Bandung, West Java, Indonesia
2 Department of Urology, Cipto Mangunkusumo, University of Indonesia, Bandung, West Java, Indonesia
3 Department of Pathology, Hasan Sadikin Hospital, Universitas Padjadjaran, Bandung, West Java, Indonesia

Date of Submission31-Dec-2018
Date of Decision05-Aug-2019
Date of Acceptance26-Aug-2019
Date of Web Publication24-Oct-2019

Correspondence Address:
Ferry Safriadi
Jl. Adipati Kertabumi No 5, Bandung 40115, West Java
Indonesia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/UROS.UROS_153_18

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  Abstract 


Purpose: This study aims to analyze the relationship between c-myc and adiponectin receptor expressions to prostate cancer staging and prove the role of c-myc and adiponectin receptors as risk factors of metastatic prostate cancer. Materials and Methods: This was a comparative study. The study sample consisted of 35 cases of metastatic prostate cancer and 35 cases of organ-confined prostate cancer. c-myc and adiponectin receptor expressions were examined by using immunohistochemistry and histoscore assessment with the cutoff point of 4. Chi-square and Mann–Whitney U-test were used to assess differences in c-myc and adiponectin receptor expressions. Stratification test and multiple logistic regressions were used to assess the correlation between the variables. Results: There were significant differences of c-myc expression (P = 0.000; odds ratio [OR]: 67.16 [95% confidence interval (CI): 3.820–180.50]) and adiponectin receptor expression (P = 0.001; OR: 6.0 [95% CI: 2.1–17.5]) between the two groups. The stratification test revealed that when c-myc and adiponectin receptor expressions were positive, the OR was 7.50 (95% CI: 1.827–30.783). Conclusion: c-myc and adiponectin receptors play an essential role in prostate cancer metastases. Positivity of both parameters will increase the probability of metastases.

Keywords: Adiponectin receptors', c-myc, metastases, progression, prostate cancer


How to cite this article:
Safriadi F, Sugandi S, Umbas R, Hernowo BS. The role of c-myc and adiponectin receptors in prostate cancer metastases. Urol Sci 2019;30:220-5

How to cite this URL:
Safriadi F, Sugandi S, Umbas R, Hernowo BS. The role of c-myc and adiponectin receptors in prostate cancer metastases. Urol Sci [serial online] 2019 [cited 2019 Nov 22];30:220-5. Available from: http://www.e-urol-sci.com/text.asp?2019/30/5/220/269886




  Introduction Top


Prostate cancer is currently the most prominent nonskin malignancy in Western countries and is the fourth most common malignancy in men worldwide.[1],[2] Prostate cancer is diagnosed in more than 670,000 men annually.[1],[2] Approximately 1 of 6 men in the United States (US) has prostate cancer during their lifetime, but this is lesser in many Asian countries and other developing countries. Race and dietary factors are thought to play a role in this disease.[3]

Prostate cancer is a urologic malignancy with the highest rate of bone metastases, of 65%–75%, compared to other malignancy types.[4] Complications of bone metastases/skeletal-related events (SREs) cause immobilization of patients due to severe pain, pathological fractures, vertebral compression syndrome, and hypercalcemia.[4] SRE incidence in Western countries is approximately 46%, whereas in our institution, the incidence is 15%.[5]

Bone scintigraphy is used to detect bone metastases with 95% sensitivity and 32% specificity.[4] False-positive results in bone scintigraphy are due to trauma, inflammation, and infection.[6]

c-myc gene located on chromosome 8q24 is commonly re-represented excessively or is amplified in prostate cancer metastases.[7],[8] c-myc is involved in the regulation of cell proliferation and cell death pathways. Myc protein functions as an activator of transcription by binding to other proteins such as Max through mitogen-activated protein kinases (MAPKs) pathway.[9] Research using Northern blot examination shows that the c-myc expression is five times higher in prostate cancer than in benign prostatic hyperplasia (BPH).[10] Further studies using cell culture, LNCaP, PC-3, and DU-145 concluded that the occurrence of androgen-independent growth in prostate cancer is due to the c-myc activity to maintain androgen receptor signaling despite antiandrogenic therapy, which allows neuroendocrine cells of prostate cancer to differentiate.[11]

Adiponectin is the most abundant circulating adipokine, accounting for 0.05% of the total plasma protein.[12] Plasma adiponectin reduction has been observed in obesity-related states such as type 2 diabetes, cardiovascular disease, hypertension, and metabolic syndrome.[12] Circulating adiponectin levels are inversely associated with breast, endometrial, colon, and gastric cancers risks in several studies.[13] Adiponectin, as a cell proliferation inhibitor, induces apoptosis through caspase pathway and suppression of tumor growth due to the anti-angiogenic effect through c-jun NH2-terminal kinase (JNK) pathway and signal transducer activator of transcription 3.[14] The main signal molecule that is responsible for mediating the metabolic effects of adiponectin is 5'-adenosine monophosphate-activated protein kinase (AMPK). It has implications for carcinogenesis of the prostate.[12],[15] AMPK activates p21 and p53 that inhibit the growth of tumor cells and also activates tumor suppressors by inhibiting mammalian homolog of the target of rapamycin.[15] Prostate cancer patients have lower adiponectin levels and weaker expression of its receptors than normal people and BPH patients.[16]

This study aimed to analyze the relationship between c-myc and adiponectin receptor expressions and prostate cancer staging and to prove the role of c-myc and adiponectin receptors as risk factors of metastatic prostate cancer.


  Materials and Methods Top


Patients

This comparative study was conducted between January 2009 and December 2012, involving 70 prostate cancer patients who met the inclusion criteria and agreed to participate in this study, and the Hasan Sadikin Hospital Ethical Committee approved this study (No. LB.04.01/A05/EC/009/VI/2011 on June 21, 2011). The first step of diagnosis was based on the prostate biopsy when patients have lower urinary tract symptoms with elevated prostate-specific antigen (PSA) level, abnormal digital rectal examination (DRE) findings, or bone pain. Clinical tumor staging was performed through DRE, transrectal ultrasound, prostate biopsy, and bone scintigraphy. Patients were divided into two groups: patients with organ-confined prostate cancer and those with metastases. Patients underwent computed tomography/magnetic resonance imaging before surgery or if the nomogram predicts >10% probability of pelvic node involvement. The treatment options were radical prostatectomy for the organ-confined patients and either medical or surgical castration for patients with metastases. Data of age, Body Mass Index (BMI), blood samples, and paraffin blocks were collected.

Blood examination

PSA, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride, testosterone, and blood sugar levels were examined using enzyme-linked immunosorbent assay methods.

Histopathology/immunohistochemistry

Hematoxylin and eosin staining was used for histopathologic examination of prostate biopsy, prostatectomy, and lymph node specimens. The Gleason score of both the groups was measured from the prostate biopsy specimen. The Gleason score was reconfirmed from the prostatectomy specimens in organ-confined patients. Paraffin blocks of the two groups were subjected to indirect immunoperoxidase staining using either c-myc (Abcam; rabbit monoclonal ab 32072) or adiponectin receptor (Abcam; rabbit monoclonal ab12611). c-myc staining was localized in the cytoplasm, whereas adiponectin receptors were stained on the membrane and cytoplasm. The c-myc and adiponectin receptor expressions were rated according to the intensity and distribution positivity. The criteria of intensity positivity used were as follows: 0 (negative), staining intensity the same as that of a negative control; 1 (weakly positive), light brown; 2 (moderately positive), brown; and 3 (strongly positive), dark brown. The criteria of distribution positivity used were as follows: 0 = negative, 1 ≤5% of tumor cells were stained, 2 = 5%–20% of tumor cells were stained, 3 = 21%–50% of tumor cells were stained, and 4 ≥50% of tumor cells were stained. The results of intensity and distribution positivity were combined as histoscore according to McCarty et al.[17] Histoscore = (intensity + 1) × density; cutoff point was 4. A score ≥4 indicated positivity, whereas a score <4 indicated negativity.

Statistical analysis

Differences between two groups were analyzed using the Student's t-test, Mann–Whitney U-test, and logistic regression test, with P < 0.05 being considered as significant. The statistical software used was the IBM SPSS version 17.


  Results Top


Both PSA and blood sugar levels were significantly different between the two groups. The other parameters were not significant.

c-myc expression was 100% positive in the metastases group, which was significantly different from the finding in the organ-confined group. Data revealed that patients with positive c-myc expression have 67 times higher risk of metastases than patients with negative c-myc expression.

Adiponectin receptor expression is significantly different between the two groups and was prominent in the metastases group.

c-myc and adiponectin receptors showed a significant interaction for metastases. Patients with positive c-myc expression had 7.5 times higher possibility of developing metastases compared to those with negative expression.


  Discussion Top


In the present study, we compared the c-myc and adiponectin receptor expressions between 35 cases of metastatic prostate cancer (cases) and 35 cases of organ-confined prostate cancer (controls).

The confounding variables used in this study were age, BMI, lipid profile, blood sugar, and testosterone [Table 1]. In the analysis, we found that the mean age of patients with advanced prostate cancer and those with organ-confined prostate cancer was 68.1 and 64.6 years, respectively, which do not differ significantly based on the statistic calculation. This result is not different from that of the US study that investigated patients with a mean age of 68 years.[2] The mean BMI of our patients with advanced prostate cancer and those with organ-confined prostate cancer was 22.7 ± 2.5 kg/m2 versus 22.2 ± 2.5 kg/m2, respectively, showing that our patients have normal weight. These results differ from those in literature, stating that the majority of patients are overweight or obese.[13],[16],[18] Lipid profile (total cholesterol, HDL, LDL, and triglycerides) was included to investigate the metabolic syndrome parameters. In the metabolic syndrome, prostate volume and PSA will be larger and higher.[19] In our study, cholesterol levels in both the groups did not differ significantly and were within the normal range (158 mg/dL vs. 150 mg/dL). The median HDL levels were the same (22 mg/dL) in both the groups. The LDL levels did not differ significantly (113 mg/dL vs. 105 mg/dL). The difference in median triglyceride levels between the two groups was not significant (124 mg/dL vs. 131 mg/dL), and the levels were within the normal limits. Obesity decreases testosterone levels due to the peripheral aromatization of androgens to estrogens in fat tissue. Low free testosterone levels influence the development of prostate, as this is associated with poorly differentiated carcinoma and advanced-stage prostate.[20] There was no significant difference in the testosterone level between the two groups, and the levels were within the normal limits (3.9 ng/mL vs. 3.6 ng/mL).
Table 1: Patients' characteristics, prostate-specific antigen, Gleason Score, Body Mass Index, blood sugar, lipid profile, and testosterone levels

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The prevalence of c-myc expression in this study was 75.7%, as identified in immunohistochemistry (IHC) [Figure 1], which differed from that of previous studies that reported 70% prevalence, using mRNA examination, Northern blot, fluorescence in situ hybridization (FISH), and IHC.[10],[21] The relationship between the incidence of c-myc and metastatic prostate cancer analyzed by the Student's t-test resulted in odds ratio (OR): 67.16 (95% confidence interval [CI]: 3.820–1180.50 with P = 0.000) [Table 2], indicating that c-myc plays a major role in the occurrence of metastases in prostate cancer. This result is in line with the literature suggesting that c-myc is one of the genes that play a central role in progression-metastatic prostate cancer. Their amplification or re-representation causes vascular endothelial growth factors (VEGFs) mRNA stimulation and the loss of E-cadherin function, that makes cancer cells loose and metastases.[22],[23],[24]
Figure 1: Immunohistochemistry staining of c-myc expression. (a) Strong positive, (b) negative

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Table 2: c-myc expression results

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The prevalence of adiponectin receptor expression in this study is 40% [Table 3], which is slightly higher than that reported in a previous study conducted in Athens, of 29%.[16] It is maybe because our patients have normal weight, whereas those in Athens' study were obese. Moreover, this difference in prevalence may occur due to the differences in the IHC positivity examination interpretation, as until now, there is still no agreement reached by the experts on the valuation of the standard positivity [Figure 2]. Same as Michalakis's study, the adiponectin receptor expressions were prominent in metastases group.[16] It could be the effect of adiponectin as anti-tumor which is more active in this stage.
Table 3: Adiponectin receptors expression

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Figure 2: Immunohistochemistry staining of adiponectin receptors. (a) Strong positive, (b) negative

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To investigate the interaction between c-myc and adiponectin receptor expressions, a stratification test using the Student's t-test was performed. The result presents a significant correlation (P = 0.003) between c-myc and adiponectin receptors with OR of 7.5 (95% CI: 1.827–30.783), indicating that the risk of metastatic prostate cancer is 7.5 times higher in positive patients than in negative patients [Table 4].
Table 4: Differences between the c-myc and adiponectin receptors expressions

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Based on these results, the molecular pathogenesis description of prostate cancer, especially c-myc and adiponectin receptors, in terms of the process of proliferation-progression-metastases is as follows. In prostate cancer, carcinogenesis may occur as a result of amplification or re-representation of the c-myc gene, which is a transcriptional activator that regulates several processes in the cell, including cell cycle, metabolism, and ribosome biogenesis.[25] The initial phase is proliferation, which is preceded by the amplification of c-myc. After the amplification or re-representation of c-myc, the c-myc protein synthesis increases, followed by binding to Max protein. The c-myc and Max protein bond will activate the MAPK pathways,[9] triggering the activation of Ras/Raf protein, which in turn will induce the MAPK/extracellular signal-regulated kinase (ERK) (MEK) protein. MEK will activate the ERK protein. The active ERK proteins will enter into the cell nucleus to induce c-jun gene transcription, which will result in cell proliferation. On the other hand, c-myc induces cyclin D2-Cdk4 complex, inhibiting the action of p27Kip1 proteins that play a role in resting cells in the G1 phase.[26] Cancer cells will continue to increase consequently.

Another effect of c-myc amplification is the lengthening of telomeres by regulating the expression of human telomerase reverse transcriptase and inhibiting cell growth inhibitor p16INK4a. Owing to this effect, cancer cells undergo immortalization.[27]

The proliferation of the cells causes increased oxygen consumption with a fixed supply, and it will trigger the hypoxia-inducible factor-1 (HIF-1), which, together with c-myc, maintains persistent cell transcription. In malignant cells, glucose metabolism disturbances also occur (Warburg effect). c-myc and E2F1 protein will increase the revenue and conversion of glucose to lactate by inducing genes involved in nucleotide metabolism and DNA replication.[28]

The adiponectin receptors will capture adiponectin and then work through APLL1 proteins that activate AMPK.[12],[15],[29] AMPK will activate JNK and STAT3. Thus, caspase-9 will be activated and causes apoptosis and inhibition of angiogenesis. Adiponectin activates suppressor genes such as p53, p21, and phosphatase and tensin homolog, in addition to inhibiting IKK-nuclear factor-kappa B (Ikappa B) pathway that plays a role in DNA transcription.[15],[29] The protective effect of adiponectin against c-myc is to inhibit the c-myc-cyclin D1, thereby decreasing the mRNA of cancer cells [Figure 3].
Figure 3: Process of cell proliferation-inhibition by c-myc and adiponectin – blue line: Activation, red line: Inhibition. MEK: MAPK/ERK complex, MAPK: Mitogen-activated protein kinase, ERK: Extracellular signal-regulated kinase, hTERT: Human telomerase reverse transcriptase, VEGF: Vascular endothelial growth factor, HIF-1: Hypoxia-inducible factor 1, mTOR: Mammalian target of rapamycin, PTEN: Phosphatase and tensin homologue, AMPK: Adenosine 5'-monophosphatase kinase, JNK: c-jun NH2-terminal kinase, STAT3: Signal transducer and activator of transcription 3

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The next phase is the progression of cancer cells to metastases. The process is initiated by the epithelial to mesenchymal transition state, which is marked by angiogenesis and release of malignant cells into the bloodstream or lymph. VEGF is involved in this situation through its activation using two channels, namely the c-myc-rapamycin pathway and HIF-1 pathway.[22],[23] Cancer cells released into the bloodstream or lymph are affected by the loss of the bond between the cells. Under normal circumstances, the cells are bound to each other by cell adhesion molecule, known as E-cadherin.[24] Amplification of c-myc leads to a decrease in E-cadherin function so that the bonds between the cells become loose, and eventually, the cells are detached and enter into the bloodstream or lymph [Figure 4].[30]
Figure 4: Process of metastases influenced by c-myc – blue line: activation, red line: inhibition. HIF-1: Hypoxia-inducible factor 1, VEGF: Vascular endothelial growth factor, Rb: Retinoblastoma gene

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There are several limitations in this study. First, the number of patients was limited. Second, this work was a comparative study; ideally, a prospective cohort study will give more information on a disease progression. Third, there were different specimens used, which were obtained from prostate biopsy and prostatectomy. Finally, all patients were from only one referral center in Indonesia.


  Conclusion Top


Our findings suggest that c-myc and adiponectin receptors have an essential role in prostate cancer metastases. The positivity of both parameters will increase the probability of metastases.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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