【摘要】：背景：侵襲性無功能垂體腺瘤是垂體腺瘤中較為特異的一組良性腫瘤,由于腫瘤體積較大,并侵襲周圍組織,因此臨床上將腫瘤全部切除較困難。術(shù)后放療在部分患者中可以縮小殘留腫瘤,然而也可引起垂體功能低下、視神經(jīng)病變和認(rèn)知功能障礙等并發(fā)癥。因此,藥物靶向治療成為抑制無功能垂體腺瘤生長的新方向。PI3K/Akt/mTOR信號通路與細(xì)胞的生長、代謝密切相關(guān),在腫瘤的發(fā)生發(fā)展中起重要作用。PI3K作為PI3K/Akt/mTOR通路的重要因子,分為三種類型,其中ClassI PI3K由一個(gè)催化亞基p110(p110α, p110β, p110γ和p110δ)和調(diào)節(jié)亞基構(gòu)成,其亞基做為多種腫瘤的藥物靶點(diǎn)被研究。然而在無功能垂體腺瘤中,目前尚無PI3K的亞基表達(dá)水平的研究。方法：選取2012到2014年就診于北京協(xié)和醫(yī)院神經(jīng)外科的無功能垂體腺瘤患者32例,其中侵襲性垂體腺瘤14例(男性5例,女性9例,平均年齡45.5+6.5歲),非侵襲性垂體腺瘤15例(男性9例,女性6例,平均年齡53.0+13.0歲),正常垂體組織3例(男性1例,女性2例,平均年齡58.0歲)。通過免疫組化、Western Blotting、qRT-PCR的方法研究PI3K/AKT/mTOR信號通路中PI3K的催化亞基p110α和調(diào)節(jié)亞基p85α、PTEN及其下游因子Akt在上述3組樣本中的表達(dá)變化。結(jié)果：免疫組化染色發(fā)現(xiàn),正常垂體組織p110α表達(dá)量較侵襲組(p0.05)明顯升局。PTEN蛋白在非侵襲組中表達(dá)明顯高于正常垂體及侵襲性組(p0.05)。Akt染色發(fā)現(xiàn),與正常垂體相比,侵襲組(p0.05)及非侵襲組(p0.001)陽性表達(dá)率明顯升高；非侵襲組與侵襲組相比升高更明顯(p0.01)。Western Blotting顯示p85 α蛋白在侵襲組(p0.05)中表達(dá)較正常垂體明顯升高。在qRT-PCR水平,各指標(biāo)mRNA表達(dá)水平在各分組之間無顯著差異。結(jié)論：本研究發(fā)現(xiàn),在侵襲性無功能垂體腺瘤中p110α蛋白表達(dá)是顯著降低的,p85α的表達(dá)是升高的。這對下一步PI3K靶向藥物在無功能垂體腺瘤中的研究提供實(shí)驗(yàn)依據(jù)。對于PI3K其他亞基在無功能垂體腺瘤中的表達(dá)情況,還有待進(jìn)一步研究。
[Abstract]:Background: invasive nonfunctional pituitary adenoma is a group of benign tumors in pituitary adenoma. Because of the large size of the tumor and invasion of surrounding tissues, it is difficult to remove the tumor completely clinically. Postoperative radiotherapy can reduce residual tumors in some patients, but it can also cause hypophysis, optic neuropathy and cognitive dysfunction. Therefore, drug targeting therapy has become a new direction to inhibit the growth of nonfunctional pituitary adenomas. PI3K/Akt/mTOR signaling pathway is closely related to cell growth and metabolism. PI3K, as an important factor of PI3K/Akt/mTOR pathway, is divided into three types. ClassI PI3K consists of a catalytic subunit p110 (p110 偽, p110 尾, p110 緯 and p110 未) and regulatory subunit. Its subunits have been studied as drug targets for various tumors. However, there is no study on the subunit expression of PI3K in nonfunctional pituitary adenomas. Methods: from 2012 to 2014, 32 cases of nonfunctional pituitary adenoma were selected from neurosurgery department of Peking Union Hospital, including 14 cases of invasive pituitary adenoma (male 5 cases, female 9 cases, mean age 45. 5 5 years). There were 15 cases of noninvasive pituitary adenoma (male 9 cases, female 6 cases, mean age 53.0 13.0 years) and 3 cases of normal pituitary tissue (male 1 case, female 2 cases, mean age 58.0 years). The expression of the catalytic subunit p110 偽 and the regulatory subunit p85 偽, PTEN and its downstream factor Akt of PI3K in the PI3K/AKT/mTOR signaling pathway were studied by immunohistochemical and Western Blotting,qRT-PCR methods. Results: the expression of p110 偽 in normal pituitary tissue was significantly higher than that in invasive group (p0. 05). The expression of PTEN protein in non invasive group was significantly higher than that in normal pituitary tissue and invasive group (p0. 05). Akt staining). Compared with the normal pituitary gland, the positive expression rates of p0.05 and p0.001 in invasive and non-invasive groups were significantly higher than those in normal pituitary gland. The expression of p85 偽 protein in invasive group was significantly higher than that in normal pituitary group (p0.01). Western Blotting). At the level of qRT-PCR, there was no significant difference in the expression of mRNA among different groups. Conclusion: the expression of p110 偽 protein in invasive nonfunctional pituitary adenomas was significantly decreased and the expression of p85 偽 was increased. This provides the experimental basis for the further study of PI3K targeting drugs in nonfunctional pituitary adenomas. The expression of other subunits of PI3K in nonfunctional pituitary adenomas remains to be further studied.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R736.4
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本文編號：2372426