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 تاريخ التسجيل :  Oct 2011
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افتراضي بحث رائع عن علاقة الجين بالسرطان Tumor suppressor in lung cancer 1 gene expression in epithelial ova




Tumor suppressor in lung cancer 1 gene expression in epithelial ovarian cancer
» Abstract


Objectives: Loss of Tumor Suppressor in Lung Cancer 1(TSLC1) was observed in many different cancers, but there were only limited research on TSLC1 gene and its roles in cancer suppression in ovarian cancer. This study explores the relationship between TSLC1 gene expression and the ovarian epithelial cancer. Materials and Methods: Expression levels of TSLC1 were detected by immunohistochemical staining on formal-fixed paraffin embedded pathological specimen. A total of 259 samples were collected, including 24 benign ovarian tumor and 235 malignant ovarian cancers among them. Results: Suppressed expression of TSLC1 protein was observed in 87.8% of poorly differentiated, 85.1% of moderately differentiated, and 46% of well differentiated ovarian epithelial cancers, respectively. There were none suppressed TSLC1 expression in benign ovarian tumor. Kruskal-Wallis test showed a significant association between the expression levels of TSLC1 gene and the degree of ovarian cancer differentiation (P < 0.001). Conclusions: Decreased expression of TSLC1 is associated with the differentiation in ovarian epithelial cancer. TSLC1 might be used as a molecular marker of severity in early stage ovarian cancer, and to help differentiating benign and malignant ovarian tumors.

Keywords: Gene expression, immunohistochemical staining, ovarian cancer, tumor suppressor in lung cancer 1

How to cite this article:
Qu H, Xu F, Bai Y, Si X, Yang A. Tumor suppressor in lung cancer 1 gene expression in epithelial ovarian cancer. Indian J Cancer 2016;53:8-11

How to cite this URL:
Qu H, Xu F, Bai Y, Si X, Yang A. Tumor suppressor in lung cancer 1 gene expression in epithelial ovarian cancer. Indian J Cancer [serial online] 2016 [cited 2016 Dec 25];53:8-11. Available from: http://www.indianjcancer.com/text.as.../53/1/8/180845



» Introduction رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression


Ovarian cancer is the leading cause of death from gynecologic cancers in adult women.[1] It has been reported recently that the incidence of this disease has been increasing in China.[2]

Patients are asymptomatic in early stage: Two-thirds of ovarian cancers are diagnosed after the cancer has spread.[3] Overall 5-year survival rate for ovarian cancer patients is less than 25%.[4] Serous ovarian carcinomas is a common histological type, accounting for two-thirds of epithelial ovarian cancer and 70% of all ovarian malignancies and majority of deaths.[5],[6] For clinical diagnosis, ovarian carcinoma has been categorized as well, moderately or poorly differentiated.[7]

It is very important to ascertain a novel genetic biomarker to help differentiate benign and malignant ovarian tumors in early stages, to provide therapeutic targets for cancer treatments, and also to improve overall survival rate for patients with ovarian cancer.

Tumor suppressor in lung cancer 1 (TSLC1) is located in chromosome 11q23.2. Kuramochi was first found TSLC1 as a tumor suppressor gene in non-small cell lung cancer along A594 cell lines.[8] It is also named immunoglobulin superfamily 4, spermatogenic immunoglobulin superfamily, synaptic adhesion molecule 1, or nectin-like molecule 2.[9] TSLC1 can significantly inhibit the growth of malignant tumor, participate in cell adhesion, cell movement, signal transduction and immune adjustment.[10] TSLC1 protein contains homologous structural domains belonging to members of the immunoglobulin superfamily, Nerve Cell Adhesive Molceule (NCAM) adhesion proteins, and the nectin family of Ca 2+ - independent cell-cell adhesion proteins.[8],[11]

TSLC1 is widely expressed in human tissues of cancerous tumors, synapse formation, sperm production, and plays an important role in the cancer progression process.[12],[13] It has been recently found that TSLC1 protein is lost or decreased in non-small cell lung cancer [8],[14] and many other types of malignant tumor, such as esophageal, [15] liver,[16] colon,[17] pancreas,[18] cervical,[12] nasopharyngeal.[19] Moreover, suppressed expression of TSLC1 has also been shown to be related to malignant tumor lesion, metastasis, and the cancer prognosis.[18],[19] At present, our knowledge is limited about the significance of the expression of the TSLC1 gene in ovarian tumor.

In this study, we measured the TSLC1 protein expression levels by using immunohistochemical (IHC) staining of human epithelial ovarian cancers tissues. Control group consisted of patients with benign ovarian tumor. The TSLC1 expression is correlated with histological differentiation grade in ovarian epithelial cancer.


» Materials and Methods رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression


Patients and tissue specimens

The paraffin-embedded archival pathological specimens were retrieved from 235 patients with epithelial ovarian cancers. All patients were recruited from Lanzhou University, First Affiliated Hospital, Lanzhou, China, between 1995 and 2008. The specimens were prepared at the pathology department at the hospital. The recruited patients had not received immunosuppressive treatments such as radiotherapy or chemotherapy at the time of specimen harvest.

The 235 ovarian cancer specimens were histologically confirmed, by multiple pathologists who independently confirm the histological type, as invasive serous ovarian cancer. Among them, 50 were well differentiated, 54 moderately, and 131 were poorly differentiated, respectively. In addition, 24 benign ovarian tumor patients were used as controls. The age of these patients ranged from 45 years to 58 years old, with an average of 49.6 years old.

This study was approved by the medical ethics committee of the First Affiliated Hospital of Lanzhou University.

Immunohistochemistry

IHC staining was performed using a standard streptavidin-biotin-peroxidase method strictly followed the operation procedure. The tissue samples of ovarian tumor, preserved in 4% formaldehyde solution were dehydrated and embedded in paraffin. Serial sections with 2.5 μm in thickness were baked at 65°C and wax removed, and inactivated endogenous peroxidise in 30 mL/L hydrogen peroxide for 5 min. All following steps were carried out in a moist chamber.

For antigen retrieval, tissue slides were heated two times in microwave in 10 mM citrate buffer (pH 6.0) for 5 min and incubated with rabbit monoclonal antibody against human TSLC1 (1:200 dilution; abnova, Taiwan, China), overnight at 4°C in a moist box.

After 30 min incubation with biotin labeled second antibody for 30 min at 37°C, tissue slides were incubated again with avidin-horseradish peroxidase at 37°C for 30 min, rinsed in phosphate buffer solution tween (0.1M PBS, PH 7.4, 0.5% Tween20) (PBS-T) and dyed with 3, 3-diaminobenzidin, kept at room temperature without light for 10 min and completed with the distilled water. The slides were finally counterstained with hematoxylin, dehydrated, and sealed. An ovarian cancer specimen known to express TSLC1 was used as positive control PBS instead of primary antibody was used as negative control.

Protein expression levels of TSLC1 were evaluated by microscopic (OLYMPUS, Japan) examination of stained tissue slides. Image was captured and analyzed by Image Pro-PLUS 6.0 software (OLYMPUS, Japan). The presence of cytoplasmic brown granules or cell membrane stain was both considered to be positive for TSLC1 expression. The TSLC1 IHC staining results were subdivided into three levels: (1) normal expression (>% of epithelial cells are positive for TSLC1 staining) [Figure 1a] and [Figure 1b], (2) decreased expression (25-75% of epithelial cells were positive for TSLC1 staining [Figure 1c] and (3) loss of expression (<% epithelial cells were positive for TSLC1 staining) [Figure 1d]. The TSLC1 staining was interpreted by two independent pathologists who were blinded to the identity of the samples.
رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expressionFigure 1a: Immunohistochemical staining of tumor suppressor in lung cancer 1 gene in human ovarian tissues. Normal expression of TSLC1 in benign ovarian tumor. Original magnification, ×200

Click here to viewرائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expressionFigure 1b: Immunohistochemical staining of tumor suppressor in lung cancer 1 gene in human ovarian tissues. Normal expression of TSLC1 in serous ovarian cancer (moderately differentiated). Original magnification, ×200

Click here to viewرائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expressionFigure 1c: Immunohistochemical staining of tumor suppressor in lung cancer 1 gene in human ovarian tissues. Down-regulated expression of TSLC1 in moderately differentiated ovarian serous carcinoma. Original magnification, ×200

Click here to viewرائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expressionFigure 1d: Immunohistochemical staining of tumor suppressor in lung cancer 1 gene in human ovarian tissues. Lost expression of TSLC1 in serous ovarian carcinoma (poorly diferentiated). Original magnification, ×200

Click here to view


Statistics

Statistical analysis was performed using SPSS 15.0 software (SPSS Inc., Chicago, Illinois). The association between TSLC1 protein expression, histopathological grade and age of patients were evaluated by Kruskal-Wallis test. Any differences in TSLC1 level between 2 groups was considered statistically significant if P < 0.05.


» Results رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression


TSLC1 protein expression levels in ovarian cancers

From [Table 1], we can see that 115 (87.8%) of 131 poorly differentiated ovarian cancer cases had complete (n = 104) or partial (n = 11) losses of TSLC1 protein expression; 46 (85.1%) of 54 moderately differentiated cases had 2 complete and 44 partial loss of protein expression and 23 (46%) of 50 well differentiated cases had 9 complete and 14 partial loss of protein expression. By contrast, none (0%) of 24 benign ovarian tumors had complete or partial losses of protein expression. Statistical tests showed a significant difference of TSLC1 protein expression between ovarian cancer types (benign, well differentiated, moderately differentiated, and poorly differentiated) (P < 0.001) [Table 1]. We found that normal expression of TSLC1 in benign ovarian tumors, loss of expression of TSLC1 in many of poorly differentiated ovarian cancer and down-regulated expression in most of moderately differentiated ovarian cancer. In other words, poorer differentiation of the cancerous tumor was associated with increased degree of expression suppression.
رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expressionTable 1: TSLC 1 protein expression in epithelial ovarian tumors

Click here to view



» Discussion رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression


Although the treatments for ovarian cancer have improved in recent years, mortality for ovarian cancer patients still remains high.[20] Low survival rate in ovarian cancer, in part, is due to the lack of molecular markers for early detection. Progress in the molecular biology field is to help earlier detection of the ovarian cancer would be big advancement. Better biomarkers are required to differentiate benign and malignant tumors, to better predict the disease prognosis and treat cancer through genetic targets.

In many malignant tumors, complete or partial loss of expression of TSCLI were found, The TSLC1 gene expression loss rate is 50% in breast cancer,[13] 47% in esophageal squamous cell carcinoma,[15] 44% in non-small cell lung cancer,[14] and 35% in metastasis nasopharyngeal carcinoma.[19] All of those indicate that TSLC1 is related with the progress of malignant tumor, and can be used to evaluate the prognosis of cancers.[21],[22]

Loss of TSLC1 expression in a variety of histologic type in lung cancer was related with the size of the tumor and its clinical stages.[23]

Normal expression rate of TSLC1 in a normal ovarian epithelial tissue and ovarian benign tumor epithelial tissue with benign tumor and complete loss or partial loss of expression of TSLC1 in a ovarian tumor and border epithelial ovarian cancer showed that TSLC1 gene expression is related to ovarian cancers, Thus, TSLC1 can be used as a sign in judging the cancer's malignancy degree and its prognosis; it also can be used as independent molecular marker in detecting the early stage ovarian cancers.[24]

In addition, the decreased protein expression of the TSLC1 gene might be important in conferring more aggressive behavior in ovarian carcinoma and in involving local invasion and distant metastasis.[21] Thus, TSLC1 may be used as an independent prognostic molecular marker for detecting ovarian carcinoma.[24]

Our study supports the above conclusions, that there is relationship between histological type and protein expression of TSLC1 in ovarian carcinoma. The decreased expression of TSLC1 is associated with malignancy grade of ovarian carcinoma. With increasingly poorer differentiation of cancer cells, TSLC1 protein expression also decreased or even totally suppressed. This study showed that TSLC1 might be used as a molecular marker in early stage of ovarian carcinoma to differentiate identify benign and malignant ovarian tumors, to evaluate malignancy grade of ovarian epithelial carcinoma, and to assist in prognosis. These in turn may provide an enhanced basis for ovarian cancer treatments and prolong people's lives.

» References رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

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2.Lynch HT, Casey MJ, Lynch J, White TE, Godwin AK. Genetics and ovarian carcinoma. Semin Oncol 1998;25:265-80. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

3.Motohara T, Tashiro H, Miyahara Y, Sakaguchi I, Ohtake H, Katabuchi H. Long-term oncological outcomes of ovarian serous carcinomas with psammoma bodies: A novel insight into the molecular pathogenesis of ovarian epithelial carcinoma. Cancer Sci 2010;101:1550-6. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

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7.Lurie G, Wilkens LR, Thompson PJ, Matsuno RK, Carney ME, Goodman MT. Symptom presentation in invasive ovarian carcinoma by tumor histological type and grade in a multiethnic population: A case analysis. Gynecol Oncol 2010;119:278-84. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

8.Kuramochi M, Fukuhara H, Nobukuni T, Kanbe T, Maruyama T, Ghosh HP, et al. TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer. Nat Genet 2001;27:427-30. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

9.Murakami Y. Involvement of a cell adhesion molecule, TSLC1/IGSF4, in human oncogenesis. Cancer Sci 2005;96:543-52. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

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11.Shingai T, Ikeda W, Kakunaga S, Morimoto K, Takekuni K, Itoh S, et al. Implications of nectin-like molecule-2/IGSF4/RA175/SgIGSF/TSLC1/SynCAM1 in cell-cell adhesion and transmembrane protein localization in epithelial cells. J Biol Chem 2003;278:35421-7. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

12.Yang YX, Yang AH, Yang ZJ, Wang ZR, Xia XH. Involvement of tumor suppressor in lung cancer 1 gene expression in cervical carcinogenesis. Int J Gynecol Cancer 2006;16:1868-72. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

13.Heller G, Geradts J, Ziegler B, Newsham I, Filipits M, Markis-Ritzinger EM, et al. Down regulation of TSLC1 and DAL-1 expression occurs frequently in breast cancer. Breast Cancer Res Treat 2007;103:283-91. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

14.Ito T, Shimada Y, Hashimoto Y, Kaganoi J, Kan T, Watanabe G, et al. Involvement of TSLC1 in progression of esophageal squamous cell carcinoma. Cancer Res 2003;63:6320-6. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

15.Heller G, Fong KM, Girard L, Seidl S, End-Pfützenreuter A, Lang G, et al. Expression and methylation pattern of TSLC1 cascade genes in lung carcinomas. Oncogene 2006;25:959-68. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

16.Tsujiuchi T, Sugata E, Masaoka T, Onishi M, Fujii H, Shimizu K, et al. Expression and DNA methylation patterns of Tslc1 and Dal-1 genes in hepatocellular carcinomas induced by N-nitrosodiethylamine in rats. Cancer Sci 2007;98:943-8. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

17.Borinstein SC, Conerly M, Dzieciatkowski S, Biswas S, Washington MK, Trobridge P, et al. Aberrant DNA methylation occurs in colon neoplasms arising in the azoxymethane colon cancer model. Mol Carcinog 2010;49:94-103. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

18.Hong SM, Kelly D, Griffith M, Omura N, Li A, Li CP, et al. Multiple genes are hypermethylated in intraductal papillary mucinous neoplasms of the pancreas. Mod Pathol 2008;21:1499-507. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

19.Lung HL, Cheung AK, Xie D, Cheng Y, Kwong FM, Murakami Y, et al. TSLC1 is a tumor suppressor gene associated with metastasis in nasopharyngeal carcinoma. Cancer Res 2006;66:9385-92. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

20.Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin 2007;57:43-66. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

21.Uchino K, Ito A, Wakayama T, Koma Y, Okada T, Ohbayashi C, et al. Clinical implication and prognostic significance of the tumor suppressor TSLC1 gene detected in adenocarcinoma of the lung. Cancer 2003;98:1002-7. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

22.Surace EI, Lusis E, Murakami Y, Scheithauer BW, Perry A, Gutmann DH. Loss of tumor suppressor in lung cancer-1 (TSLC1) expression in meningioma correlates with increased malignancy grade and reduced patient survival. J Neuropathol Exp Neurol 2004;63:1015-27. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

23.Okugawa K, Hirakawa T, Fukushima K, Kamura T, Amada S, Nakano H. Relationship between age, histological type, and size of ovarian tumors. Int J Gynaecol Obstet 2001;74:45-50. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression

24.Yang G, He W, Cai M, Luo F, Kung H, Guan X, et al. Loss/Down-regulation of tumor suppressor in lung cancer 1 expression is associated with tumor progression and is a biomarker of poor prognosis in ovarian carcinoma. Int J Gynecol Cancer 2011;21:486-93. رائع علاقة الجين بالسرطان Tumor suppressor lung cancer gene expression





 

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