Research ArticleExperimental Studies

Decreased Expression of SATB2 Associates with Tumor Growth and Predicts Worse Outcome in Patients with Clear Cell Renal Cell Carcinoma

AGNIESZKA SLIWINSKA-JEWSIEWICKA, ANNA E. KOWALCZYK, BARTLOMIEJ E. KRAZINSKI, JANUSZ GODLEWSKI, PRZEMYSLAW KWIATKOWSKI, JOLANTA KIEWISZ, JEDRZEJ GRZEGRZOLKA, PIOTR DZIEGIEL and ZBIGNIEW KMIEC
Anticancer Research February 2018, 38 (2) 839-846;

Abstract

Background/Aim: SATB2 (special AT-rich sequence-binding protein 2) is a DNA-binding protein that is involved in transcriptional regulation and chromatin remodeling. SATB2 protein has been described as a promising novel marker in several human cancers. Patients and Methods: This study compared SATB2 expression in tumor and matched unchanged renal tissues collected from 57 patients with clear cell renal cell carcinoma (ccRCC). SATB2 mRNA levels were determined by quantitative polymerase chain reaction, while SATB2 protein expression was estimated by immunohistochemistry. Moreover, the associations between SATB2 expression in ccRCC samples and clinicopathological and survival data of the patients were investigated. Results: The mRNA level of SATB2 was lower in tumor tissues than in samples of corresponding unchanged kidney. Although the average immunoreactivity of SATB2 protein did not differ significantly between cancer cells and epithelial cells of proximal convoluted tubules, the decreased SATB2 expression in tumor specimens inversely correlated with the size of primary tumor and predicted worse patients' outcome. Conclusion: The results of the presented study suggest the tumor-suppressing function of SATB2 and that the expression level of this protein can be considered a potential prognostic factor in ccRCC.

Renal cell carcinoma (RCC) is diagnosed in more than 200,000 individuals worldwide each year, accounting for approximately 2% of all cancers (1). RCC is a clinicopathologically-heterogeneous disease and comprises of several histological subtypes that are phenotypically and genetically different. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC, representing approximately 70-80% of all RCC cases (2). ccRCC carries a worse prognosis than the other histological variants, such as papillary and chromophobe RCC (3). It seems that this is the result of the highly invasive character of ccRCC and that micro-metastases can even develop during early stages of disease. Moreover, ccRCC is highly resistant to radiation, chemotherapy, and targeted therapy (4). The five-year survival rate of ccRCC is approximately 5-15% (5). It is thought that initiation and progression of RCC are a consequence of the accumulation of genetic alterations involving numerous various genes (4, 6), therefore, identification and investigations of differentially expressed genes are needed to test their usefulness as molecular markers and therapeutic targets.

Special AT-rich sequence-binding protein-2 (SATB2) gene encodes a nuclear matrix associated protein, which is a transcription factor and epigenetic regulator involved in chromatin remodeling and regulation of gene expression (7, 8). SATB2 participates in growth and developmental processes. It controls the activity of transcription factors that regulate craniofacial development as well as osteoblasts' and cortical neurons differentiation (9, 10). This protein also modulates immunoglobulin gene expression (11). Moreover, few studies have indicated that SATB2 may play an important role in the development and progression of some types of cancers (12-20), and the level of its expression can be used as a prognostic factor, although the prognostic value of SATB2 expression depends on cancer type (12, 13, 16-19). Furthermore, the results of investigations are controversial. Some studies showed higher SATB2 expression in tumor tissues compared to non-cancerous specimens and that SATB2 functions as an oncogene (12-15), while other reports revealed a tumor suppressive role of SATB2 and reduced amount of this protein in cancer tissues (16-20). Thus, the level of SATB2 expression and its function seems to be cancer-type specific.

So far, the prognostic significance of SATB2 expression in ccRCC was investigated only in one study (21), whose authors, due to the small number of patients included, suggested the need for further studies to confirm their findings. Therefore, the main purpose of our research was to compare SATB2 gene expression in samples of the ccRCC tissue and matched unchanged kidney and analyze correlations between the expression level of SATB2 and clinicopathological features, as well as overall survival (OS) in the cohort of Polish patients. Quantitative real-time polymerase chain reaction (qPCR) was used to assess SATB2 mRNA levels, while an immunohistochemical (IHC) method was applied to determine the expression of SATB2 protein in the tested samples.

Materials and Methods

Ethics. The present study was carried out in accordance with the ethical standards, and approved by the Bioethics Committee of the University of Warmia and Mazury in Olsztyn (decision no. 22/2010 and 4/2010). Written informed consent regarding the participation in the study and use of tissue was obtained from each patient.

Patients and the collection of tissue samples. The specimens were collected at the Hospital of the Ministry of Internal Affairs and Administration in Olsztyn (Poland) from 2010 to 2014. The study included 57 patients with ccRCC (28 men and 29 women; aged 64.05±10.93 years, mean±SD; range=27-83 years). None of the patients had a history of other tumor or suffered from other serious disease. The demographic and clinical characteristics as well as survival data of all patients were gathered. Median follow-up time was 40.8 months.

Two types of samples from each patient subjected to radical nephrectomy were obtained immediately after surgical resection: (i) ccRCC tissue, and (ii) matched macroscopically unchanged renal cortex tissue from a distant part of the resected kidney. Tissue samples for qPCR analysis were frozen in liquid nitrogen and stored at −80°C, while specimens for routine histological and immunohistochemical evaluation were fixed in neutral 4% buffered-formaldehyde and further processed into paraffin blocks. The tumor stage was characterized by a pathologist according to the TNM system (AJCC Cancer Staging; American Joint Committee on Cancer) (22). The degree of tumor malignancy was determined using the Fuhrman nuclear grading system (23).

Total RNA extraction, reverse transcription and qPCR. Total RNA was extracted from all studied tissues using a Total RNA Prep Plus kit (A&A Biotechnology, Gdynia, Poland), according to the procedure provided. Isolated RNA was quantified with spectrophotometry (NanoDrop 1000, NanoDrop products, Wilmington, DE, USA). Reverse transcription was carried out using the High-Capacity cDNA Reverse Transcription Kit (Life Technologies - Applied Biosystems, Foster City, CA, USA). Reactions were performed according to the manufacturer's instructions, and resulting complementary DNAs (cDNAs) were diluted 6-fold with nuclease-free water and stored at −20°C to be used as templates in qPCR analysis.

Quantification of SATB2 gene expression was carried out using ABI 7500/7500 Fast Real-Time PCR System (Life Technologies – Applied Biosystems, Foster City, CA, USA). TATA box binding protein (TBP) and peptidylprolylisomerase A (PPIA) genes were applied as an internal control to normalize the transcript levels of SATB2. The levels of SATB2, TBP and PPIA cDNAs in collected isolates were determined using TaqMan®Fast Advanced Master Mix and a respective TaqMan® Gene Expression Assay (for SATB2: Hs00392652_m1, TBP: Hs00427620_m1 and PPIA: Hs99999904_m1; all: Life Technologies – Applied Biosystems, Foster City, CA, USA) according to the manufacturer's instructions and using the following conditions: polymerase activation for 20 sec at 95°C, followed by 40 cycles of denaturation at 95°C for 3 sec and annealing/extension at 60°C for 30 sec. The ΔΔCt method (24) was applied to determine the fold differences in SATB2 expression between the matched samples of ccRCC and unchanged kidney. Fold increase above 1 (2−ΔΔCt>1) indicated SATB2 overexpression in ccRCC tissue, and fold decrease under 1 (2−ΔΔCt<1) indicated SATB2 down-regulation.

Immunohistochemistry and evaluation of immunoreactivity. SATB2 immunostaining in ccRCC and unchanged renal tissues was performed according to the previously described method (25) on 4 μm-thick paraffin sections using the Autostainer Link48 (DakoCytomation, Glostrup, Denmark). Rabbit monoclonal primary antibody directed against SATB2 (1:100, Anti-SATB2 antibody EPNCIR130A, ab92446, Abcam, Cambridge, UK) was applied, while the negative controls were performed by omitting the primary antibody.

The SATB2 immunostained sections were evaluated using Olympus BX53 light microscope (Olympus, Tokyo, Japan) by a pathologist in a blinded manner regarding the clinicopathological data of the patients. The scoring system for nuclear SATB2 immunoreactivity was based on the percentage of SATB2-positive ccRCC cells or proximal convoluted tubules (PCTs) epithelial cells (0, absence of staining; 1, when 1-10% cells were immunoreactive; 2, 11-50%; 3, 51-80% and 4, >80%).

Based on median expression values, ccRCC cases which showed expression scores ≤1 were regarded as having ‘low’ expression, whereas scores >1 were regarded as ‘high’ SATB2 expression.

Statistical analysis. Statistical analyses were carried out using Prism software (v. 6.04; GraphPad, La Jolla, CA, USA). The differences in SATB2 mRNA and protein levels between matched ccRCC and unchanged kidney tissues were examined by the Wilcoxon matched-pairs test. The correlations between the clinicopathological characteristics and SATB2 gene expression were analyzed by the Fisher's exact test or Spearman correlation. The log-rank test was used to evaluate the statistical significance of differences in OS between groups of patients. Survival curves were plotted using Kaplan-Meier method. In all performed analyses, the results were considered statistically significant at p<0.05.

Figure 1.
Figure 1.

SATB2 mRNA levels in the tumor and unchanged kidney tissues of clear cell renal cell carcinoma (ccRCC) patients (n=57) as determined by quantitative polymerase chain reaction. (A) SATB2 mRNA levels in tumors of individual ccRCC patients are shown in relation to the SATB2 mRNA content in matched unchanged renal tissues. (B) The average expression of SATB2 mRNA (mean±SEM) in ccRCC tissues is shown in relation to the value obtained for unchanged kidney tissues (1.0); ***p<0.0001.

Results

SATB2 mRNA expression is decreased in ccRCC. SATB2 mRNA was found in all studied tissue samples of ccRCC patients. The average expression of SATB2 mRNA was significantly decreased in ccRCC when compared to unchanged kidney tissues (0.67±0.21 vs. 1.00±0.32, respectively, p<0.0001; Figure 1). Among the 57 tumor specimens tested, the relative SATB2 mRNA level (ccRCC vs. matching unchanged kidney tissues) was decreased in 43 (75.4%) tumors and increased in 14 (24.6%) specimens. The relative expression of SATB2 did not correlate with any of the tested clinicopathological parameters (Table I).

Heterogenous nuclear SATB2 immunohistochemical staining in ccRCC tissues. SATB2 immunoreactivity was observed mainly in the nuclei of ccRCC cells and epithelial cells of PCTs and only several specimens revealed a weak immunostaining of SATB2 in the cytoplasm of examined cells (Figure 2). Among 57 ccRCC specimens tested, nuclear immunoreactivity of the SATB2 protein was low in 33 (57.9%) and high in 24 (42.1%) cases. (Table I). The average levels of nuclear SATB2 immunoreactivity did not differ significantly between ccRCC and PCT epithelial cells (1.26±0.18 vs. 1.59±0.08, respectively, p=0.1178; Figure 3). However, the negative correlation was found between the level of the SATB2 immunoreactivity and primary tumor size (r=−0.3413, p=0.0094; Table I).

OS of patients is associated with the SATB2 immunoreactivity level in ccRCC. To estimate the prognostic significance of the studied gene expression, all patients were followed up for the median time of 40.8 months. During this observation period, 21/57 (36.8%) patients deceased (Table II).

Decreased nuclear immunoreactivity of SATB2 in ccRCC specimens (hazard ratio (HR)=2.89; p=0.0298; Figure 4), higher Fuhrman grade (p<0.0001), AJCC stage (p=0.0019), and tumor size (p=0.0114), presence of distant metastases (p=0.0008) and invasive status of the disease (p=0.0302) were found to be associated with worse patient prognosis (Table II). The SATB2 mRNA expression level did not correlate with patients' OS (p=0.5859; Table II; Figure 4).

Discussion

SATB2 regulates gene expression by modulating chromatin architecture and by functioning as a transcriptional factor (7-9), and in this way, it is involved in a variety of important biological as well as pathological processes. In addition to its roles in development processes, especially in craniofacial morphogenesis (9), SATB2 seems to be associated with pathogenesis of some types of cancers. It was shown that SATB2 participates in pancreatic carcinogenesis inducing cellular transformation, stemness and epithelial to mesenchymal transition (EMT), and inhibition of its expression suppresses these activities (12). It was found that SATB2 promotes invasion and proliferation of human hepatocellular carcinoma cells (15), as well as chemoresistance of head and neck squamous cell carcinoma cells (14). However, the opposite results were also reported. SATB2 suppressed cell invasion, metastasis and EMT-related proteins in non-small cell lung cancer cells (19), furthermore, it inhibited proliferation and tumor progression ability of Hep2 (laryngeal squamous cell carcinoma cell line) cells (18). Exogenous expression of SATB2 in colorectal cancer cells also suppressed cell proliferation, colony formation and in vivo tumor growth (26). These findings indicated the cancer type-specific functions of SATB2, thus, it can be expected that also SATB2 gene expression levels differ depending on the kind of cancer.

View this table:
Table I.

Associations between clinicopathological features of ccRCC patients and the relative mRNA expression of SATB2 gene in kidney tumor tissues or SATB2 nuclear immunoreactivity in cancer cells.

Increased expression of SATB2 gene in the tumor compared to control non-cancerous tissues was observed in pancreatic (12), breast (13), hepatocellular (15) and head and neck squamous cell (14) cancers, while its decreased expression was revealed in colorectal (26), laryngeal (18) and esophageal squamous cell (16) cancers. SATB2 is a member of the SATB family proteins and it is closely related to another protein abnormally expressed in ccRCC - SATB1 (27). To date, the evaluation of SATB2 expression in association with its prognostic value in ccRCC has been limited to one study (21). Our finding of significantly reduced SATB2 mRNA levels in ccRCC compared to matching unchanged kidney tissues is in line with the results of Guo et al. (21); however, in contrast to the mentioned authors, we did not observe the difference in SATB2 protein immunoreactivity between ccRCC and PCTs epithelial cells, although the average immunoexpression of SATB2 protein in ccRCC tended to be lower than in unchanged kidney tissue. Our observations suggest that in ccRCC, dysregulation of some mechanisms suppresses the SATB2 expression. Previous studies established that SATB2 regulation may vary by cell type (28), and microRNAs (miRNAs, miRs) and distant regulatory elements play a significant role in controlling the expression of SATB2. It was found that AS021, a short interspersed repetitive sequence and a type of retrotransposon, acts as a distal enhancer resulting in an increase of SATB2 expression (28, 29). Another regulator, Runx2, is a transcription factor that promotes SATB2 expression by blocking the miR cluster 23a-27a-24-2, which negatively regulates SATB2 (28, 30). Moreover, it was also found that Runx2 inhibits miRNA-31, another negative regulator of SATB2 (28, 31). Results of some studies have indicated that miR-31 (32) and miR-182 (33) repress SATB2 expression in colorectal cancer, while miR-211 (15) negatively regulates SATB2 in hepatocellular cancer. We did not investigate mechanisms underlying the observed downregulation of SATB2 expression in ccCRC; however, published data confirm expression of miR-182 and especially miR-31 in ccRCC (34). Thus, the examination of the effects of mentioned miRs on SATB2 expression in ccRCC remains for further analysis.

Figure 2.
Figure 2.

Evaluation of SATB2 protein expression in clear cell renal cell carcinoma and unchanged renal tissues by immunohistochemistry. (A) Intense nuclear and cytoplasmic immunohistochemical staining of SATB2 protein in the proximal tubules cells of unchanged kidney cortex, (B) dominant nuclear and low cytoplasmic SATB2 immunoreactivity in ccRCC cells, (C) low nuclear immunostaining in tumor cells. (D) Negative controls were performed by omitting the primary antibody. Magnification ×200.

Figure 3.
Figure 3.

Nuclear expression of SATB2 protein in the tumor and unchanged kidney tissues of clear cell renal cell carcinoma (ccRCC) patients (n=57) determined by immunohistochemistry. (A) The level of nuclear SATB2 immunoreactivity in tumors of individual ccRCC patients is shown in relation to the level of SATB2 immunostaining in matched unchanged renal tissues. (B) The average nuclear immunoreactivity of the SATB2 protein in epithelial cells of proximal convoluted tubules (PCT) and ccRCC cells. Bars represent mean±SEM. NS, Not significant.

Figure 4.
Figure 4.

Kaplan–Meier survival curves of 57 clear cell renal cell carcinoma (ccRCC) patients regarding the levels of (A) SATB2 mRNA expression and (B) nuclear immunoreactivity of SATB2 protein in ccRCC tissues.

View this table:
Table II.

Analysis of overall survival of ccRCC patients in relation to their clinicopathological characteristics and SATB2 expression.

Guo et al. (21) reported the correlation between low levels of SATB2 expression in ccRCC and high AJCC staging and Fuhrman grade. We did not confirm these findings; however, our study revealed the relationships between decreased nuclear SATB2 protein levels in ccRCC and greater tumor size. We demonstrated that the hazard ratio for patients whose ccRCC tissues showed reduced SATB2 immunohistochemical staining was almost three times higher than in patients with increased SATB2 immunoreactivity. Results of our investigation indicating the association of decreased SATB2 expression in tumor tissues with poor prognosis are in line with the study of Guo et al. (21). These findings support the clinical significance and tumor suppressive role of SATB2 and suggest that altered expression of SATB2 gene may promote progression of ccCRC. The relationship between downregulated SATB2 gene expression in tumor tissues and unfavorable clinicopathological parameters and prognosis was also observed in colorectal (17), laryngeal (18), non-small cell lung (19) and esophageal squamous cell (16) cancers, however, opposite results were reported for breast (13) and head and neck squamous cell (14) cancers. Thus, the role of SATB2, its expression level and association with clinical parameters is cancer-type specific.

In summary, down-regulated expression of SATB2 in ccRCC compared to non-cancerous renal tissues and correlations between decreased SATB2 expression and greater tumor size, as well as poor prognosis suggest that in ccRCC SATB2 can be considered a tumor suppressor and potential prognostic factor. Further studies are needed to explain the exact mechanisms by which SATB2 is involved in the development and progression of ccRCC.

Acknowledgements

This study was supported by statutory grant of University of Warmia and Mazury in Olsztyn.

Footnotes

  • ↵* These Authors contributed equally to this study.

  • Conflicts of Interest

    The Authors declare no conflicts of interest.

  • Received November 23, 2017.
  • Revision received December 10, 2017.
  • Accepted December 11, 2017.

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Decreased Expression of SATB2 Associates with Tumor Growth and Predicts Worse Outcome in Patients with Clear Cell Renal Cell Carcinoma
AGNIESZKA SLIWINSKA-JEWSIEWICKA, ANNA E. KOWALCZYK, BARTLOMIEJ E. KRAZINSKI, JANUSZ GODLEWSKI, PRZEMYSLAW KWIATKOWSKI, JOLANTA KIEWISZ, JEDRZEJ GRZEGRZOLKA, PIOTR DZIEGIEL, ZBIGNIEW KMIEC
Anticancer Research Feb 2018, 38 (2) 839-846;
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