Expression Of TSHR,ER And CyclinD1 In Differentiated Thyroid Carcinoma And Their Significance

Thyroid carcinoma is the most familiar thyroid malignant tumor, and differentiated thyroid carcinoma (DTC) includes papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma, FTC), both account for 80%⁹0% of total thyroid carcinomas. Given early surgical therapy, survival rate of 5 years may reach to above 75%, even reach to 97% if given anti-thyroid-stimulating hormone treatment after operation. The occurrence rate of the thyroid neoplasm tends to ascend in recent years, so it is necessary to investigate deeply the pathogenesis of DTC.Thyroid-stimulating hormone receptor (TSHR) is a membrane receptor of thyroid follicle cell, after conjugation with TSHR, thyroid-stimulating hormone (TSH) can adjust and control the function of thyroid and accelerate the growth of thyroid follicle cell; TSHR plays an important role in the adjustment of thyroid. TSH and TSHR together adjust and control the excretion of T₃ and T₄, meanwhile that accepted negative feedback adjustment from T₃ and T₄. It is reported that the number of the thyroid adenoma are the same as TSHR's transcript of normal thyroid. The lower the differentiation degree of the malignant tumor cell, the less of TSHR's transcripting number. The tumor cell then transform towards de-differentiation, TSHR transcription tends to disappear. mRNA level of TSHR and malignant degree of tumor present strong negative correlation, high-level TSHR gene expression relates to highdifferentiation of the tumor. In the course of gradual progress, tumor's abnormal form increase, which will weaken or lose the function and characteristic of origin tissue, e.g. the expression of the peculiar antigen weakens or disappears. TSHR is the main receptor to adjust and control the growth and differentiation of the thyroid gland cell, whose unusually expression is the important reason of acquired character, heredity or congenital thyroid gland disease. Studies have been shown, TSHR gene mutation has something to do with the occurrence of autoimmunity thyroid disease, TSH resist , high TSH blood disease of thyroid gland with normal function and thyroid tumor, etc.The adjustment and controlling abnormally of cell cycle causes the cells to proliferate continuously, which is the biological foundation that the tumor occurs. The core of multiple factors to adjust and control cell cycle is cyclin and cyclin dependent kinase(CDK). CyclinD is one of the important members of Cyclin family, compound through conjugating with CDK4/CDK6 will control cells to pass G1 phase, starting Gl phase is the key of cell cycle. CyclinD includes Dl, D2, and D3. The relationship between CyclinDl and tumour is the clearest in three kinds of CyclinD. CyclinDl has been verified as protooncogene. As the most important positive control gene in the process of restricting to adjust and control Gl phase, which expressed excessively and adjusting and controlling wrongly may cause cell cycle to adjust and control unusually, thus the tumor occurs.Estrogen receptor (ER) with biological activity is the peculiar conjugated protein that makes corresponding estrogen produce biological effect. The estrogen may strengthen the carcinogenic factor through some direct or indirect mechanisms after combining with ER, and promote CyclinDl to express excessively, namely the estrogen accelerates thyroid tumor cell to proliferate, thus facilitate the thyroid neoplasm to occur and develop. There is no obvious relationship between the occurrences of the thyroid carcinoma and sex before ten years old. After this, the occurrence rate of the female's thyroid neoplasm is higher obviously, because the female's endogenous estrogenic secretion begins to increase about ten years old, sothe secretions increase and enhancement of function of the estrogen might have something to do with the occurrence of thyroid neoplasm. Clinically, thyroid adenoma and DTC have been often detected on female, and the incidence of 20⁴0 years old female are most high, estrogen level at this moment are relatively high, these instructed that the thyroid gland disease related to estrogen's function. People find that CyclinDl and ER is positive correlation among breast cancer and think that the estrogen adjusts CyclinD1's expression among tumor, and it is found in the breast cancer patient with positive estrogen receptor, CyclinDl level declined after having treated with estrogen inhibitor. In the non-target organ research, some scholars made exploring treatment with antiestrogen, eg. Colon cancer, pancreas patient with ER positive and have made better curative effect. Other scholars treated the positive CyclinDl melanoma patient with antisence oligonucleotide and also had better effect. At present, although there are some reports about the relationship between ER and DTC, the concrete function mechanism of ER needs to study further during the occurrence, development of the thyroid gland disease. There is no any report yet about the expression of TSHR, ER, cyclinDl among DTC and the research of relevant relationship.For this reason, we measure the expression of TSHR, ER and cyclinDl in the thyroid gland constitution with immune group SP, which is helpful for the clarification of disease mechanism of thyroid gland; offer the reliable theoretical foundation for clinical treatment, diagnosis of the disease, prognosis determination.Material and methodWe have collected 89 full specimens from surgical resection in Pathology Dept. of First Affiliated Hospital of Zhengzhou University of 2000- 2003, all the sections were formalin-fixed and paraffin-embedded, each has detailed clinical data, the HE staining sections were affirmed and histopathologic types were classified by two pathologists. 43 cases for DTC (39 cases Papillary thyroid carcinoma, PTC; 4 cases Follicular thyroid carcinoma, FTC), 7 male, 36 female, age between 14 to 75 yearsold, average age is 45.22±15.39 years old. All the cases were not performed any chemotherapy, radiotherapy and immunization therapy before operation. 14 patients had stage I tumor, 20 stage II, 8 stage III, 1 stage IV according to the TNM stage classification of UICC; 16 lymph gland metastasis, 27 non-lymph gland metastasis; 30 cases for thyroid adenoma, 5 male, 25 female, age between 17 to 78 years old, average age is 48.98±14.85 years old. Choose 16 cases with normal thyroid tissues around thyroid adenoma as common comparison that were verified by pathologists. Protein expression of TSHR, ER and CyclinDl in the sections of 43 DTC, 30 cases thyroid adenomas and 16 normal thyroid tissues were detected by immunohistochemistry streptavidin peroxides methods. Having been analyzed by SPSS 10.0 statistical software, the results a =0.05 were considered as significant test level.ResultFirst, the expression of TSHR, ER, CyclinDl in normal thyroid gland tissue, thyroid adenoma and DTC1.1 The expressing character of TSHR in the thyroid tissueNormal thyroid gland tissue, thyroid adenoma and DTC tissue can be expressed fully, expressing position lie in cytoplasm, but expressing intensity are different. The expression of thyroid adenoma tissue is similar with normal thyroid tissue, 88.37% (38/43) expression in DTC is similar with normal tissue, but 11.63% (5/43) expression are lower than normal thyroid tissue.1.2 The expressing character of ER and CyclinDl in the thyroid tissueThe expression of ER in normal thyroid tissue, thyroid adenoma and DTC is orientated as the cytoplasm mainly, orientated as the nucleus on a small quantity. The positive rate of ER in DTC is 53.5% (23/43), notably higher than 26.7% (8/30) in the thyroid adenoma and 12.5% (2/16) in the normal thyroid tissue (P< 0.05). The expression of CyclinDl in the normal thyroid tissue is negative. The expression of thyroid adenoma and DTC are orientated as the cytoplasm mainly, orientated as the nucleus on a small quantity. The expression rate of DTC is 65.1% (28/43), notablyhigher than 36.7% (11/30) in the thyroid adenoma (P< 0.05).Second, The relationship between the expression of TSHR, ER and CyclinDl in DTC,clinical data and pathology character2.1 The relationship between ER expression in DTC, clinical data and pathology character68.0% (17/25) ER positive rate in DTC in those patients who are less than 45 years old person is notably higher than 33.3% (6/18) (P<0.05) of patients who are or more than 45 years old; 63.9% (23/36) ER positive rate of female are notably higher than 0.00% (0/7) (P<0.05) of male. There was no obvious relationship between the positive expression of ER and size of tumor, the number of focus, tumor staging and lymph node metastasis (P> 0.05), etc.2.2 The relationship between the expression of CyclinDl in DTC, clinical data and pathology character83.3%(15/18) positive rate of CyclinDl in DTC in those patients who are or more than 45 years old is notably higher than 52.0%(13/25) of patients who are less than 45 years old (P<0.05); 87.5% (14/16) positive rate of CyclinDl with lymph node metastasis is notably higher than 51.9% (14/27) without lymph node metastasis (P< 0.05), There was no obvious relationship between the positive expression of CyclinDl and sex, size of tumor, the number of focus and tumor staging (P> 0.05), etc. 23 The relationship between the expression of TSHR in DTC, clinical data and pathology characterThere is relationship between TSHR expression in DTC and tumor of grade, with or without lymph node metastasis and age (P< 0.05), I — II stage is no low-expression, III^IV is low expression 55.56% (5 / 9). Low expression group has always lymph node metastasis, while non- lymph node metastasis group has no low expression. Low expression patients are or more than 45 years old, while the patients who are less than 45 years old have no low expression. There was no obvious relationship between the positive expression of TSHR and sex and size of tumor, the number of focus (P> 0.05).Third, the relationship between TSHR, ER and CyclinDl3.1 Relationship between CyclinDl and ER in DTCThere is obvious positive correlation relationship between positive expressions of CyclinDl and positive expression of ER( x2=6.661, P=0.010).3.2 Relationship between CyclinDl and TSHR in DTCThere is no obvious relevant relationship between the positive expressions of CyclinDl and TSHR in DTC ( x2= 1.542, i>=0.214) . 33 Relationship between ER and TSHR in DTCThere is no obvious relevant relationship between the positive expressions of ER and TSHR. ( *2=0.028 P=0.868) .Conclusion1. The expression of ER relates to DTC patient's age, sex, differentiation thyroid carcinoma may be a kind of estrogen dependence tumor;2. The expression of CyclinDl relates to DTC patient's age, lymph node metastasis, there is obvious positive correlation relationship between the positive expression of CyclinDl and of ER, the estrogen may promote the growth of the tumor through the influence on cell cycle;3. The low expression of TSHR relates to DTC patient's age, lymph node metastasis and pathology staging. With DTC being converted to de-differentiation, TSHR expression may disappear; the differentiation thyroid carcinoma may be TSH dependence tumor;4. Detection for the TSHR, ER, CyclinDl is helpful to further classify the pathogenesis of DTC.