Investigation of the roles of TGFβ1, CUG2, TGFBI genes, and thiol-disulfide balance on prostate cancer and metastasis

Muhammet Yusuf Tepebaşı; Okan Sancer; Pınar Aslan Koşar; Alim Koşar; İlter İlhan

doi:10.1515/tjb-2022-0259

Article Open Access

Investigation of the roles of TGFβ1, CUG2, TGFBI genes, and thiol-disulfide balance on prostate cancer and metastasis

Muhammet Yusuf Tepebaşı , Okan Sancer , Pınar Aslan Koşar , Alim Koşar and İlter İlhan

Published/Copyright: June 9, 2023

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From the journal Turkish Journal of Biochemistry Volume 48 Issue 3

Abstract

Objectives

Transforming growth factor-beta (TGFβ1) is involved in tumorigenesis and metastasis. It provides this effect both by disrupting the thiol-disulfide balance and through the cancer-upregulated gene (CUG2) and transforming growth factor beta-induced (TGFBI) genes in the signaling pathway. In this study, the roles of TGFβ1 and related genes, as well as thiol-disulfide balance, in the formation of prostate cancer and metastasis were investigated.

Methods

Tissue samples were taken from 33 benign prostatic hyperplasia (BPH) and 35 prostate cancer (PC) patients to determine the Gleason score and metastasis. TGFβ1, CUG2, and TGFBI gene expression levels were measured by RT-PCR. Serum prostate specific antigen (PSA) levels were measured in patients, and PSA density (PSAD) was calculated. Total thiol and native thiol measurements in serum were performed spectrophotometrically, and disulfide was calculated.

Results

In patients with prostate cancer and metastases, PSA and PSAD levels were high, while total thiol and native thiol were significantly lower (p<0.05). TGFβ1, CUG2 and TGFBI gene expression levels were higher in patients with prostate cancer and metastases and were negatively correlated with total thiol and native thiol (p<0.001).

Conclusions

As a result of our study, we determined that the increase in TGFβ1, CUG 2 and TGFBI in prostate cancer plays an important role in cancer formation and metastasis by disrupting the thiol-disulfide balance.

Keywords: CUG2; metastasis; prostate cancer; TGFβ1; TGFBI; thiol-disulfide

Introduction

Prostate cancer is the second-most common type of cancer in men all over the world, including in our country. In cancer statistical studies, it has been stated that the worldwide prevalence of prostate cancer is 7.3 % and the mortality rate is 3.8 % [1]. Today, in the diagnosis of prostate cancer, generally the serum prostate-specific antigen level (PSA), PSA density (PSAD), rectal examination, and prostate biopsy methods are used [2]. Studies on the early diagnosis and metastasis of prostate cancer have revealed that genetic factors and oxidative stress are effective in the development of this disease [3].

Increased reactive oxygen species in the cell cause mutations in DNA, contributing to cell proliferation, cancer development, and the metastasis process [4]. Thiols are powerful antioxidant molecules that contain a sulfhydryl group and protect the organism against the damage caused by oxidative stress by reducing the formation of reactive oxygen species or accelerating their inactivation [5]. Thiol-disulfide balance has critical roles in antioxidant defense, detoxification, apoptosis, regulation of enzyme activities, and mechanisms of transcription and cellular signal transduction [6].

Transforming growth factor-beta (TGFβ), which has been determined to play an active role in many cancers, is known to have pleiotropic effects on cell proliferation, differentiation, migration, and survival. TGFβ exerts a tumor suppressor effect at the onset of tumorigenesis through the inhibition of cellular growth and induction of apoptosis [7]. During tumor progression, tumor cells play a role in tumor survival as they lose their susceptibility to TGFβ-mediated growth arrest and retain their ability to migrate to the epithelial-mesenchymal transition (EMT), which is associated with increased invasiveness and metastases [8]. It has been determined that TGFβ expression is increased in PC patients with poor prognoses and plays an important role in cancer progression [9]. In addition, studies have shown that increased TGFβ causes increased oxidative stress, which contributes to cancer formation and metastasis. TGFβ has three isoforms, TGFβ1, 2, and 3, and it has been stated that TGFβ1 is the most abundant isoform in humans [10, 11]. It has been determined that TGFβ activity is exerted by cells that secrete TGFβ in a latent form, which is non-covalently associated with the delay-associated peptide (LAP) to form the small latent TGFβ complex (SLC). The SLC consists of disulfide-linked homodimers of TGFβ and LAP and may itself be disulfide-linked to a latent TGFβ binding protein (LTBP), forming the large latent TGFβ complex (LLC). LTBP plays a role in revealing its biological effect by directing TGFβ to the extracellular matrix [12, 13]. Furthermore, Jobling et al. stated that the oxidative modification that leads to latent TGFβ activation occurs in LAP and that redox-mediated activation is limited to the LAP/TGFβ1 isoform. They explained this effect of TGFβ1 as containing a redox switch specific to the 273-order methionine amino acid in its structure [14]. Cancer upregulated gene 2 (CUG2) is an essential centromere component for kinetochore function during cell division and has been identified as a candidate gene with oncogenic activity in tissues such as the colon, lung, and ovary and playing an important role in tumorigenesis [15, 16]. Also, recent studies have reported that CUG2 overexpression induces cancer stem cell-like phenotypes, including an increase in cell migration, invasion, sphere formation, and resistance to anticancer drugs via the upregulation of TGFβ signaling [17]. The transforming growth factor beta-induced (TGFBI) gene induced by TGFβ, also called βIGH3 or keratoepithelin, encodes the TGFBI protein localized to the extracellular matrix. Normally, the expression of TGFBI is found in fibroblasts, keratinocytes, and muscle cells [18, 19]. It has been determined that TGFBI plays a role in cell-matrix interaction and cell migration, and that increased expression levels may be more aggressive and prone to metastasis in colon and pancreatic cancers [20, 21].

Based on the relevant literature, we investigated the contribution of TGFβ1 and related genes (CUG2 and TGFBI), known as an extracellular sensor of oxidative stress in tissues with disulfide bonds in their structure, to the formation of prostate cancer and metastasis, as well as their effects on the thiol-disulfide balance.

Materials and methods

Study design and participants

The patient groups in this study were composed of patients diagnosed with prostate cancer (PC) and benign prostatic hypertrophy (BPH) who applied to the urology outpatient clinic of Süleyman Demirel University Medical Faculty Hospital. The tissue samples obtained as a result of the biopsy performed on the patients were taken to Eppendorf and stored at −80 °C. Biopsy samples from 33 BPH and 35 PC patients were collected. Demographic information about the patients was obtained as a result of anamnesis. Gleason scoring and tumor lymph node metastasis (TNM) staging were performed by expert clinicians. The structural differentiations of tissues obtained from prostate biopsy specimens as a result of histopathological evaluation were used to calculate Gleason scores. As a result of the analysis, a score of 2–10 was made (≤6 moderately differentiated cancer cells, ≥7 badly differentiated cancer cells). TNM staging is based on PET and PET-CT combined (PET-CT) characteristics, including the size of the main tumor (T category), whether the cancer has spread to nearby lymph nodes (category N), and whether the cancer has spread to other parts of the body (category M) (TNM 1&2 tumor limited to prostate, TNM 3&4 tumor invaded from prostate tissue). Prostate volumes were determined by transrectal ultrasonography (TRUS).

Biochemical analysis

PSA serum levels were measured using the Beckman Coulter DxI 800 (Beckman Coulter, USA) device and chemiluminescence method. PSAD was obtained by dividing the serum PSA value by the prostate volume. Total thiol and native thiol measurements in serum were performed spectrophotometrically using the Beckman Coulter AU5800 autoanalyzer (Beckman Coulter, USA) and Real Assay Diagnostics Commercial Kits (Cat. No: RL0185, Gaziantep, Turkey). The disulfide bonds were first reduced with sodium borohydride to form free functional thiol groups. To prevent the reduction of DTNB (5,5′-dithiobis-(2-nitrobenzoic) acid), the unused reducing sodium borohydride was consumed and removed with formaldehyde and determined after the determination of all thiol groups, including reduced and natural thiol groups. reaction with DTNB. The blood levels of native thiol (–SH) and total thiol (–SH + –S–S–) were measured. The number of dynamic disulfide bonds was calculated by taking half of the difference between total and native thiol groups. %CV values are 4 , 5, and 13 % for concentrations of 29.1, 16.0, and 7.15 mmol/L, respectively. The detection limit of measurement was 2.8–4,000 mmol/L [22].

RT-qPCR analyzes

The RNA isolation of tissue samples was performed with the GeneAll Ribospin RNA Isolation Kit (Cat. No:305101, Seoul, Korea) according to the manufacturer’s protocol. The amount and purity of the RNAs obtained were measured with the BioSpec-nano nanodrop (Shimadzu Ltd., Kyoto, Japan) device. The Atlas Biotechnology TM cDNA Synthesis Kit (Cat. No: C03-01-05, Atlas Biotechnology, Turkey) was used to synthesize cDNA in a thermal cycler according to the protocol. Primer designs were made by detecting specific mRNA sequences and testing possible primer sequences using the NCBI website (Supplementary Table 1). Expression levels of genes were measured in a Biorad CFX96 (California, USA) real-time PCR instrument using an A.B.T.™ 2X qPCR SYBR-green master mix (Cat. No: Q03-01-01, Atlas Biotechnology, Turkey). The actin B gene was used as a housekeeping gene in the study. The reaction mixture was prepared according to the manufacturer’s protocol. The resulting reaction mixture was placed in a real-time qPCR device with thermal cycling determined according to the kit manufacturer’s protocol, and each sample was studied in 3 replications. PCR conditions were as follows: initial denaturation at 95 °C for 300 s (1 cycle), denaturation at 95 °C for 15 s, and annealing/extension at 60 °C for 30 s (40 cycles).

Statistical analyses

The sample size was determined by G power analysis, taking into account the numbers in previous studies. The Kolmogorov-Smirnov test was used in statistical analyses to determine normality distributions. The Mann–Whitney U, or Independent Samples T-test, was used to compare the groups based on their normality distribution. The Cq values of target genes were determined, and the formula 2 ^–ΔΔCq was used to evaluate their relative expression levels. Spearman’s correlation analysis was used to evaluate the relationship between variables. Multivariate linear regression analysis was performed to determine the effects of the parameters. In addition, the area under the curve (AUC) was calculated to determine the diagnostic sensitivity of the parameters, and the cut-off values were determined by drawing the ROC curve. p<0.05 results were considered significant. SPSS 18 was used as a statistical analysis program.

Results

There were 33 BPH and 35 PC patients in our study. There were 15 patients with PC who had histopathologically well-differentiated Gleason scores 6 after biopsy and did not spread to nearby lymph nodes or elsewhere in the body in the groups we formed. There were 20 patients with poor differentiation and a Gleason score ≥7. There were 25 patients in TNM 1&2 stages with tumor formation that did not extend beyond the prostate, but there were 10 patients in TNM 3&4 stages with extraprostatic invasion. While there were 10 patients in the group with prostate tissue invasion or distant metastasis in patients with prostate cancer, there were 25 patients in the non-metastasis group.

In our study, the age, serum PSA and PSAD values of patients with BPH and PC were determined. As a result of the statistical analysis, there was no significant difference in terms of age between BPH and PC patients (p=0.320).

When we compared serum PSA and PSAD levels in BPH and PC patients, we found a significant increase in PC patients (p=0.001 and p=0.001). There was a statistically significant increase in serum PSA and PSAD levels in the 7≥ group groups we formed in patients with prostate cancer based on Gleason scoring (p<0.001 and p=0.001). In addition, there was a statistically significant difference in serum PSA and PSAD levels in the TNM2&3 group (p=0.005 and p=0.028). When we compared PSA and PSAD levels in metastasizing and non-metastatic groups, we found statistically significant differences in the metastasizing group (p=0.002 and p=0.015) (Table 1).

Table 1:

Distribution of age and biochemical parameters in all groups.

		PSA value, ng/mL	Prostate volume, mL	PSAD, ng/mL	Total thiol, μmol/L	Native thiol, μmol/L	Disulfide	Age, years
BPH (n=33)		4.44 (3.81)	103.8 ± 43.0	0.04 (0.03)	435.7 ± 28.1	411.7 ± 24.7	12.4 ± 5.21	64.0 ± 6.79
PC (n=35)		10.2 (11.7)^c	67,9 ± 25.9^a	0.09 (0.21)^a	372.7 ± 25.0^a	346.1.7 ± 28.2^a	13.3 ± 4.65	66.1 ± 7.59
Gleason score (n=35)	≤6 (n=15, 43 %)	4.91 (4.19)	67.0 ± 15.7	0.06 (0.05)	389.0 ± 21.9	362.8 ± 25.5	13.9 ± 3.76	65.2 ± 8.57
Gleason score (n=35)	≥7 (n=20, 57 %)	16.2 (10.9)^c	68,5 ± 31.9^a	0.28 ± 0.21^a	360.4 ± 20.0^a	333.5 ± 23.5^a	13.4 ± 5.33	66.8 ± 6.93
Metastasis (n=35)	Yes (n=10, 29 %)	17.6 ± 7.27^b	63.2 ± 29.7^a	0.30 ± 0.17^a	350.4 ± 19.3^a	319.9 ± 15.9^a	15.2 ± 4.69	66.8 ± 5.27
Metastasis (n=35)	No (n=25, 71 %)	6.04 (9.23)	70 ± 24.4	0.08 (0.13)	381.3 ± 22.8	356.5 ± 26.4	12.5 ± 4.43	65.8 ± 8.43

BPH, benign prostatic hyperplasia, PC, prostate cancer, normally distributed data were given as mean ± SD, and non-normally distributed data were given as median (IQR). PSA, prostate specific antigen, PSAD, PSA density. ^ap<0.033, ^bp<0.002, ^cp<0.001.

Total thiol, native thiol, and disulfide levels were used in the evaluation of oxidative stress. When we compared BPH and PC patients, total and native thiol were statistically significant, but there was no significant difference in disulfide levels (p<0.001, p<0.001, and p=0.446, respectively). In the groups formed according to Gleason scoring, total and native thiol were significantly decreased in the group with a Gleason score ≥7 (p<0.001, p=0.001, respectively), while no significant change was detected in disulfide (p=0.833). When the total thiol, native thiol, and disulfide levels were evaluated in the metastasis and non-metastasis group, it was found that total and native thiol were significantly decreased in the metastasis group (p=0.002 ve p=0.001), but there was no change in the disulfide levels (p=0.078) (Table 1).

The mean and standard deviation (SD) of the Cq values of TGFβ1, CUG2, and TGFBI genes, which were normalized and referenced to the β-Actin gene, were calculated and statistically analyzed. According to these results, expression levels of TGFβ1, CUG2, and TGFBI genes were found to be significantly increased in PC patients compared to BPH patients (p<0.001, p<0.001, and p<0.001, respectively) (Table 2). In PC patients, TGFβ1, CUG2, and TGFBI genes were found to increase 4.8, 4.6, and 2.6 fold, respectively (Figure 1). Expression levels of TGFβ1, CUG2, and TGFBI genes were compared in groups formed as ≤6 and 7≥ according to Gleason’s score in prostate cancer patients. As a result of our statistical analysis, we found that TGFβ1, CUG2, and TGFBI genes were significantly increased in the 7≥ group (p<0.001, p<0.001, and p<0.001, respectively) (Table 2). According to these results, 1.9, 1.7, and 2.4 fold increases were found in TGFβ1, CUG2, and TGFBI genes in patients with Gleason scores ≥7, respectively (Figure 1). When we compared the expression levels of TGFβ1, CUG2, and TGFBI genes in PC patients with and without metastasis, we found a significant difference (p<0.001, p<0.001, and p<0.001, respectively) (Table 2). According to these results, we found that TGFβ1, CUG2, and TGFBI genes increased by 2.0, 1.9, and 2.0 fold, respectively, in the metastasizing group (Figure 1).

Table 2:

Expression levels of TGF β, CUG2 and TGFBI genes in BPH and PC patients as well as in groups formed according to Gleason scoring, TNM staging and metastasis.

	BPH	PC	≤6 Gleason scoring	≥7 Gleason scoring	Non-metastasis	Metastasis	p-Value
TGF β1	1.13 ± 0.51	5.43 ± 2.82	3.59 ± 1.29	6.82 ± 2.88	4.25 ± 2.04	8.37 ± 2.35	p<0.001
CUG2	1.09 ± 0.54	5.06 ± 2.00	3.57 ± 1.28	6.18 ± 1.69	4.11 ± 1.37	7.44 ± 1.17
TGFBI	1.10 ± 0.66	2.83 ± 1.68	1.58 ± 0.69	3.78 ± 1.59	2.22 ± 1.44	4.37 ± 1.22

Results were normalized with ACTB housekeeping gene. Cq values are expressed as mean ± SD TGF β1, transforming growth factor-beta 1; CUG2, cancer upregulated gene; TGFBI, transforming growth factor beta induced.

Figure 1:

Graphs of the relative fold change of expression levels of TGFβ1, CUG2, and TGFBI genes in all groups. BPH, benign prostatic hyperplasia; PC, prostate cancer; TNM, tumor lymph node metastasis; NM, non-metastasis; M, metastasis.

ROC analysis was performed to determine the prognosis, severity, effect on metastasis, and specificity of the biochemical and gene-level parameters that we studied (Supplementary Tables 2 and 3). ROC curves of the parameters were drawn to determine BPH and PC disease (Figure 2). ROC curves of the parameters were drawn in the metastasizing and non-metastasis groups (Figure 3).

Figure 2:

ROC curve graph of parameters in BPH and PC patients. BPH, benign prostatic hyperplasia; PC, prostate cancer; PSA, prostate specific antigen; PSAD, PSA density; TGFβ1, transforming growth factor-beta 1; CUG2, cancer upregulated gene; TGFBI, transforming growth factor beta induced.

Figure 3:

ROC curve graph of parameters in metastasis and non-metastasis groups. PSA, prostate specific antigen; PSAD, PSA density; TGFβ1, transforming growth factor-beta 1; CUG2, cancer upregulated gene, TGFBI, transforming growth factor beta induced.

A multivariate linear regression analysis of TGFβ1, CUG2, TGFBI, total thiol, native thiol and disulfide parameters was performed. As a result of the analysis, it was found that a significant regression model F (4, 63) = 130.9, p<0.001) and 89 % of the variance in the dependent value (R² _adjusted=0.89) were explained by the independent variables. Accordingly, increase in CUG2 increases TGFβ1 positively, (β=0.39, t(63)=5.08 p<0.001). Increase in TGFβ1 increases TGFBI positively (β=0.48 t(63)=7.3 p<0.001). In addition, it was determined that the increase in TGFβ1 had a negative effect on total thiol and native thiol, but had no effect on disulfide levels (β=−0.155 t(63)=−2.6 p=0.012, β=−0.737 t(63)=−8.85 p<0.001 and β=0.074 t(63)=1.74 p=0.086 respectively).

As a result of the correlation analysis, we determined that CUG2 and TGFBI were positively correlated and significantly increased in all groups due to the increase in TGFβ1 (r=0.89 p<0.001, r=0.86 p<0.001), and total thiol-native thiol levels decreased in correlation with each other in all groups (r=−0.695 p<0.001, r=−0.701 p<0.001). No significance was found in disulfide levels (p>0.05).

Discussion

Although prostate cancer is quite common in the world, it is very important to determine the genes that cause this cancer in terms of early diagnosis, the application of treatment methods, and the effectiveness of treatment. In our study, serum PSA levels and prostate volume were determined in patients with BPH and PC, and PSAD was calculated. In addition, the effects of oxidative stress on the TGFβ1 signal pathway in prostate cancer were evaluated using total thiol, native thiol, and disulfide. Afterward, the expression levels of TGFβ1, CUG2, and TGFBI genes were examined, and their effects on cancer formation were investigated. In addition, it was tried to determine whether these genes are associated with poor prognosis in groups formed according to Gleason scoring, and metastasis in PC patients. In our study, no statistically significant difference in age was found in BPH and PC patients, as well as in PC patient groups.

Although cancer detection rates were found to decrease in biopsies performed after high serum PSA levels in prostate cancer, studies have revealed that PSA and PSAD levels are effective parameters in cancer detection and metastasis [23], [24], [25]. In addition, in studies related to PSAD obtained by proportioning prostate volume and serum PSA levels, PSAD levels were found to be higher in PC patients when BPH and PC patients were compared [26]. In our study, when we compared PSA and PSAD levels in BPH and PC patients, we found that PC patients had significantly higher levels. In addition, when we compared PSA and PSAD levels in PC patients with Gleason scoring and metastasizing-non-metastasing groups we determined that they increased significantly in patients with poor prognosis.

Studies have shown that TGFβ, which plays a role in cancer formation, acts in two different ways by acting as a tumor suppressor in some cases and as an oncogene in some cases [7]. In a study by Reis et al. in 2011, it was reported that TGFβ gene expression was significantly higher in prostate cancer patients with a Gleason score of 7≥ and showed a poor prognosis [27]. In another study by Sun et al. in 2019 with prostate cancer cell lines, it was determined that TGFβ expression increased in cancer cell lines [28]. In addition, studies on the relationship between TGFβ and oxidative stress have shown that TGFβ increases oxidative stress and plays a role in tumorigenesis and cancer progression [10]. When we compared TGFβ1gene expression levels in BPH and PC patients in our study, it was 4.8 fold higher in PC patients. In addition, in the groups we formed, TGFβ1 gene expression levels increased 1.9, and 2.0 fold in the Gleason score 7≥, and metastasizing groups, respectively. These results showed that the increase in the expression levels of the TGFβ1 gene is effective in tumor formation and metastasis in parallel with the publications.

It has been determined in lung cancers that the CUG2 gene interacts with NPM1 in the TGFβ pathway and provides SP1 and Smad 2/3 interaction, which in turn increases TGFβ expression [16]. In addition, it has been revealed that the CUG2 gene is overexpressed in ovarian, colon, liver, and lung cancers and plays an important role in tumor formation, and it has been determined that TGFβ signaling is required for CUG2-mediated epithelial-mesenchymal transition (EMT) and has a synergistic effect [17]. When we compared CUG2 expression levels in BPH and PC patients in our study, we found that it increased 4.6 times in PC patients. In addition, we found that CUG2 expression levels increased 1.7 fold in the 7≥ group according to Gleason scoring, and 1.9 fold in the metastasizing group. We determined that this increase in CUG2 expression levels contributes to cell proliferation and metastasis by increasing TGFβ1.

Studies have shown that increased expression levels of the TGFBI gene induced by TGFβ are effective in cancer formation [29]. Chen et al. in a study conducted in 2017, it was reported that TGFBI activation causes poor prognosis in patients with prostate cancer [30]. Shareef et al. in another study, it was reported that increased levels of TGFBI were effective in the invasion of prostate cancer cells and tumor growth [31]. In our study, we found that TGFBI expression levels increased 2.6 times in PC patients. In addition, we found that TGFBI gene expression levels increased significantly in groups ≥7 according to Gleason scoring, and metastasizing groups. This showed us that the TGFBI gene contributes to cell proliferation, invasion, and metastasis by the studies.

The effects of oxidative stress on cancer formation and metastasis have been demonstrated by previous studies [32]. In the publications on prostate cancer and oxidative stress, it has been demonstrated that oxidative stress plays a role in the formation and metastasis of prostate cancer [33]. In addition, it has been stated in the publications that the increase in TGFβ in cancers causes increased oxidative stress levels or increased oxidative stress causes an increase in TGFβ levels [10]. In a study on thiol balance in prostate cancer, it was stated that thiol balance was impaired in prostate cancer patients [34]. In our study, when we analyzed the oxidative stress over the thiol balance, we found that total and native thiol decreased significantly in PC patients, but there was no change in disulfide levels. In addition, while total and native thiol were significantly lower in ≥7, and metastasizing groups according to Gleason scoring, we could not detect any change in disulfide levels.

Conclusions

As a result of our study, we determined that the increased expression levels of CUG2, TGFβ1 and TGFBI genes in prostate cancer disrupted the thiol-disulfide balance and consequently contributed to tumor formation and metastasis by causing an increase in EMT. This made us think that these genes and thiol-disulfide parameters are important in the evaluation of tumorigenesis and metastasis in prostate cancer, but further clinical studies are required.

Corresponding author: Muhammet Yusuf Tepebaşı, Department of Medical Genetics, University of Süleyman Demirel, Isparta, 32300, Türkiye, Phone: +90 0246 211 94 04, Fax: +90 0246 211 37 14, E-mail: gultepe74@windowslive.com

Research funding: None declared.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Consent form was obtained from all patients participating in the study.
Ethical approval: This study was approved by Isparta Süleyman Demirel University Medical Faculty Ethics Committee (Dated:05 November 2021, No: 308).

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Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/tjb-2022-0259).

Received: 2022-11-24

Accepted: 2023-04-07

Published Online: 2023-06-09

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

https://doi.org/10.1515/tjb-2022-0259

Keywords for this article

CUG2; metastasis; prostate cancer; TGFβ1; TGFBI; thiol-disulfide

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BY 4.0