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Original Article Aberrant Promoter Methylation of SH3GL2 Gene In Int J Clin Exp Pathol 2015;8(11):15442-15447 www.ijcep.com /ISSN:1936-2625/IJCEP0016096 Original Article Aberrant promoter methylation of SH3GL2 gene in vulvar squamous cell carcinoma correlates with clinicopathological characteristics and HPV infection status Bo Li, Yinghui He, Xue Han, Shitai Zhang, Yan Xu, Yang Zhou, Zixuan Song, Ling Ouyang Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China Received September 13, 2015; Accepted October 23, 2015; Epub November 1, 2015; Published November 15, 2015 Abstract: Objective: This study attempted to examine the methylation status of SH3GL2 gene in different types of human vulvar lesions and its correlation with clinicopathological parameters. Methods: Immunohistochemical analysis was used to identify the expression status of SH3GL2 in vulvar squamous cell carcinoma (VSCC), vulvar in- traepithelial neoplasia (VIN) and benign vulvar squamous epithelium tissues. Bisulfite genomic sequencing method was used to detect methylation status of the SH3GL2 gene. Clinicopathological correlation of the alterations was analysed by the chi-square tests. Results: Immunohistochemical analysis showed expression of SH3GL2 in VSCC was significantly downregulated than that in VIN and normal vulvar tissues. In accordance with higher frequency of methylation status in SH3GL2, statistical analysis showed methylation status of SH3GL2 was closely related to tumor TNM stage (P=0.003), but not related to age, tumor volume, tumor differentiation, lymph node metastasis and VIN grade. High-methylation status of SH3GL2 showed significant association with HPV infection status. Conclu- sions: Our results indicated that the methylation status of SH3GL2 gene was associated with the TNM staging and HPV infection status of VSCC, suggesting that it might play a synergistic role in the development of VSCC. Keywords: SH3GL2, methylation, vulvar squamous cell carcinoma Introduction urothelial carcinoma [5], ovarian cancer [6], head and neck squamous cell carcinoma [7] Vulvar squamous cell carcinoma (VSCC) is one and is involved in inactivation of the SH3GL2 of the malignant tumor which severely do harm gene expression. Epigenetic silencing of to women’s health, accounting for 80%-90% in SH3GL2 gene by promoter hypermethylation is female vulva malignant tumors. A large propor- frequently shown as an important mechanism tion of VSCC and intraepithelial neoplasias (VIN) are associated with HPV infection, mainly in regulation of intracellular signal transduction type 16 and 18 [1]. Previous study we have pathway [8]. However, the expression status of demonstrated that a loss of chromosome 9P22 SH3GL2 gene and its role in VSCC pathogene- as frequent genetic changes in VSCC samples sis have not yet been elucidated. In this study, [2]. SH3GL2 gene is located at 9p22, contain- we analyzed SH3GL2 methylation status and ing 9 exons, encoding 352 amino acid protein, explored its relation to VSCC progression and which has a C-terminal SH3 domain (amino HPV infection status. acid residues 295-344) [3]. SH3GL2 mainly through the SH3 domain protein and other Materials and methods downstream proteins plays an important bio- logical role in cell proliferation, differentiation Tissue samples and other physiological functions in combina- tion [4]. Loss of SH3GL2 has been reported as 35 cases of VIN and 52 cases of VSCC (Including a prognostic factor in several cancers, such as 11 cases of para-carcinoma tissue) were Aberrant promoter methylation of SH3GL2 Figure 1. Immunohistochemical findings. SH3GL2 protein showed cytoplasm staining in vulva normal tissue (A) and vulvar intraepithelial neoplasia (B), negative staining in VSCC (C). (Original magnification ×200, scale bar, 300 μm). stage II, 20 cases of stage III; lymph node metastasis 13 cases, without lymph node metastasis 39 cases. 35 cases of VIN include Low- grade squamous intraepithe- lial lesion (VIN 1) 16 cases and High-grade squamous intraepithelial lesion (VIN 2/3) 19 cases. All of the enrolled patients underwent curative surgical resection without having chemotherapy or radi- ation therapy. The study was approved by the Medical Research Ethics Committee of China Medical University and the informed consent was obtained from all pa- tients. Immunohistochemistry stain- ing The specimens were formalin- Figure 2. Examples of direct sequencing chromatogram. Bisulfite treatment. fixed and paraffin-embedded. A. Methylation was found in vulvar squamous cell carcinoma. B. Methylation was found in vulva normal tissue. Serial sections 4-μm thick were cut and mounted on aminopropyltriethoxysilane- obtained from the Department of Obstetrics coated glass slides. The sections were incubat- and Gynecology, Shengjing Hospital affiliated ed with the monoclonal mouse anti-human with China Medical University from 2005 to antibody directed against SH3GL2 (diluted 2013. TNM-staging and grading were assessed 1:100, Santa Cruz company) at 4°C overnight according to the International Federation of and were then treated with 3% H2O2 and 5% Gynecology and Obstetrics (FIGO, 2009) stag- rabbit serum at 37°C for 1 h. Next, the sections ing system and The WHO Classification of were incubated with the secondary antibody Tumours of Female Reproductive Organs. 52 and streptavidin-peroxidase complex for 30 cases of VSCC include Keratinizing carcinomas min (SP kit, MaiXin technologies company, 36 cases, non-Keratinizing carcinomas 8 China). Slides were visualized using 3,3-diami- cases，Verrucous carcinomas 4 cases; Basal nobenzidine. Sections were stained with non- cell carcinoma 4 cases; tumor diameter <2 cm specific antibodies to provide a negative con- 16 cases, ≥2 cm 36 cases; Clinical pathologi- trol for each reaction. Staining intensity was cal stage show 14 cases of stage I, 18 cases of scored semiquantitatively from 0 to 3 (0= nega- 15443 Int J Clin Exp Pathol 2015;8(11):15442-15447 Aberrant promoter methylation of SH3GL2 Table 1. The correlation between SH3GL2 protein levels Statistical analysis and gene methylation in different types of vulvar tissues SPSS 16.0 statistical software was SH3GL2 expression VSCC χ2 P value used for data analyzing and processing: Positive Negative Data was given as mean ± SE. Statistical SH3GL2 methylation level 0.000 analysis was performed using Student’s Methylation 6 22 17.2 t-test for unpaired samples and compar- No methylation 19 5 58 ing the differences of SH3GL2 protein expression levels in VSCC, VIN and para-cancer. Pearson correlation analy- tive, 1= weak positive, 2= strong positive). The sis was used to evaluate the relationships percentage of positive staining showed in the between the expression of SH3GL2 and gene cytoplasm staining was respectively scored as methylation in VSCC and cancer-adjacent nor- 0, 1, 2 (0= negative, 1-50%=1, 51-75%=2, mal tissues. The χ2 test was used to analyze the ≥76%=3). The product of these two scores as relationships between SH3GL2 expression and the final score for each sample staining, Score clinicopathological features and HPV infection ≤1 was considered negative expression, while status in VSCC. All P values less than 0.05 were Score >1 was considered Positive expression. considered statistically significant. Methylation assay-bisulfite genomic sequenc- Results ing PCR (BSP) combined with TA clone for sequencing Immunohistochemical results Genomic DNA was isolated from tissue sam- SH3GL2 protein was mainly expressed in the ples with a DNA extraction reagent kit (Bioteke, cytoplasm. SH3GL2 Protein expression was Beijing, China) to carry out bisulfite treatment, positive in all 11 cases of cancer-adjacent nor- so that unmethylated cytosine (C) was convert- mal tissues. The rate of positive SH3GL2 pro- ed to thymine (T), and methylated C unchanged. tein expression in VSCC and VIN was 48.08% The process was according to the manufactur- (25/52) and 65.71% (23/35), respectively er’s protocol, and quantified. (Figure 1). SH3GL2 Protein expression was sig- nificantly lower compared with normal vulva BSP reaction PCR amplification of DNA was epidermal cells, and the difference was statisti- modified as a template. Sequences of meth- cally significant (χ2=9.995, P=0.001). The posi- ylation-specific primers in the exon 2 of SH3G- tive rate in VSCC was much lower than that in L2 gene were: 5’-TAGTTTTYGGGGGTAGGAAT-3’ VIN, but the difference was not statistically sig- (forward), downstream: 5’-CACCRACATAATA CA- nificant (χ2=2.631, P=0.080). AAAAACC-3’ (reverse). The conditions for PCR amplification were at 40 cycles of 94°C for 40 MSP results s, 56°C (annealing) for 40 s, then 72°C for 40 s. SH3GL2 abnormal gene methylation was detected in 28/52 (53.8%) cases of VSCC, Cutting gel block containing the target DNA while only 2 cases (18.2%) in cancer-adjacent fragment from electrophoresis plate, using vulva tissues (Figure 2). SH3GL2 promoter DNA Purification Kit (Qiangen company) to methylation rates in VSCC was significantly recover purified PCR product, TA cloning and higher than the control group (P<0.05). SH3GL2 sequencing the PCR product accurately deter- expression levels in the methylation negative mined the methylation state in DNA sequences group were higher than that in the methylation CpG sites. The process was according to the positive group. There was negative correlation manufacturer’s protocol. between SH3GL2 protein levels and gene methylation (χ2=17.258, P=0.000) (Table 1). It CpG site unmethylated cytosine (C) converted appeared that SH3GL2 protein downregulated
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