2014-01-012024-05-16https://scholars.lib.ntu.edu.tw/handle/123456789/666921摘要：研究目標: 釐清BCL10細胞核轉位在常見癌症之可能生物意義及分子致病機轉。研究背景: BCL10係從具有t(1;14)(p22;q32) 染色體轉位之黏膜相關性淋巴組織 (MALT) 淋巴癌細胞中被發現。隨後， BCL10 被發現存在於正常 T 或 B 細胞之細胞質，並負責傳遞細胞表面抗原與T或B細胞受體結合所產生的訊息，最後造成NF-B的活化。最近我們證實BCL10核內表現可預測胃 MALT淋巴癌及胃瀰漫大細胞B細胞淋巴癌 (DLBCL) 之幽門桿菌非依賴性 (J Clin Oncol 2004;22:3491-97; Blood 2005;106:1037–41; J Pathol 2007;211:296-304)。我們更進一步發現TNF-alpha可向上調節BCL10表現，並造成BCL10細胞核內轉位，同時藉由抑制BCL10基因可進一步減少TNF-alpha所導致NF-kappaB之轉錄能力 (J Biol Chem 2006; 2006;281:167-75; Ann Surg 2008;247:265-9; Cancer Chemother Pharmacol 2011;68:1387-95)。除了TNF-alpha外，我們最近證實BAFF (TNF 家族成員) 之過度表現與BCL10之核內表現有高相關性，且抑制BAFF和NF-B之活性，可抑制BCL10之核內轉位 (Blood 2008; 112:2927-34; Ann Hematol 2010;89:431-6; Genes Chromosomes Cancer 2011;50:908-21).。我們更進一步發現BCL10核內轉位可活化AΚT/mTOR之訊息傳遞，進而減少mTOR抑制劑 (Everolimus) 對侵襲性淋巴癌細胞之毒殺效果 (Eur J Cancer 2011;47:1244-57)。初步研究成果:我們最近發現藉由小干擾RNA（small interfering RNA；siRNA）來抑制BCL10，可阻斷NF-kappaB和cyclin D1之訊息傳遞路徑，並進一步有效抑制子宮頸癌細胞株生長；同時BCL10之核內轉位與子宮頸癌之高惡性度組織型分化有關，並與細胞核內NF-kappaB表現和cyclin D1表現有高度相關性 (Gynecol Oncol 2012, in revision)。在初步的實驗中，亦證實BCL10之核內轉位與局部侵犯型口腔癌、胰臟癌、乳癌和非小細胞型肺癌之較差預後有關。在乳癌和胰臟癌細胞株之實驗中，我們證實藉由活化NF-kappaB之依賴基因和存活相關基因，可持續活化BCL10核內轉位之相關訊息傳遞，並進一步促進這些癌細胞株之生長和存活。研究假說:我們認為BCL10之過度表現與核內轉位，與發炎所誘發之NF-kappaB訊息傳遞息息相關，因此BCL10核內轉位可能向上調節及活化NF-kappaB，而進一步導致這些常見癌症之癌細胞過度生長和惡化。為了證實此假說，我們將分析BCL10核內轉位，和其本身所調控之相關訊息傳遞和轉錄基因，是否在這些常見癌症之致癌機制中扮演其重要生物意義。研究特殊目標:[1]釐清BCL10核內轉位在常見癌症 (例如乳癌、非小細胞型肺癌、胰臟癌及子宮頸癌) 之分子致病機制及生物意義中所扮演角色之研究。[2]探討與BCL10核內轉位相關之BCL10磷酸化位置、BCL10結合的核蛋白和BCL10所調控轉錄基因，並進一歩確認BCL10細胞核轉位之訊息傳遞路徑及其生物意義。[3]進一步釐清BCL10核內轉位在常見癌症之藥物抗藥性和放射線抵抗性之分子致病機制，並研究修飾BCL10核內轉位之訊息傳遞路徑相關基因，和 BCL10所調控轉錄基因來治療BCL10過度表現之癌症。預期研究結果: 藉由此研究， 我們將 (1)充分釐清及了解BCL10核內轉位在這些常見癌症之分子致癌機制及生物意義。(2) 發展具有相當潛力且極重要之治療策略來治療具BCL10核內轉位之常見癌症。<br> Abstract: Objectives: To clarify the underlying mechanisms of BCL10 nuclear translocation in the biologic significance and molecular pathogenesis of endemic cancers.Background: BCL10 was originally identified and cloned from mucosa-associated lymphoid tissue (MALT) lymphoma cells with chromosomal translocation t(1;14)(p22:q32). Later, BCL10 was found to express in the cytoplasm of normal T and B cells to relay antigen receptor-mediated signals, which culminate to activate NF-kB. We have recently demonstrated that nuclear expression of BCL10 predicts H. pylori-independence of gastric MALT lymphoma and diffuse large B-cell lymphoma (DLBCL) (J Clin Oncol 2004;22:3491-97; Blood 2005;106:1037–41; J Pathol 2007;211:296-304). We further found that TNF-alpha up-regulates of BCL10 expression and induces its localization to nucleus, and depletion of BCL10 suppresses TNF-alpha-induced NF-kB transcriptional activity (J Biol Chem 2006; 2006;281:167-75; Ann Surg 2008;247:265-9; Cancer Chemother Pharmacol 2011;68:1387-95). In addition to TNF-alpha, we have recently demonstrated that overexpression of BAFF (B-cell activating factor belonging to the TNF family) is closely associated with BCL10 nuclear translocation, and inhibition of BAFF subsequently suppresses the nuclear expression of BCL10 (Blood 2008; 112:2927-34; Ann Hematol 2010;89:431-6; Genes Chromosomes Cancer 2011;50:908-21). Furthermore, we found that BCL10 nuclear translocation activates the AKT/mTOR signaling pathway and further decreases the inhibition of cell viability of aggressive lymphoma cells to mTOR inhibitor (Everolimus) (Eur J Cancer 2011;47:1244-57).Preliminary results: We recently demonstrated that the inhibition of BCL10 by small interfering RNA (siRNA) inhibits the viability of cervical cancer cells through down-regulating NF-kB and cyclin D1; and BCL10 nuclear expression is closely associated with both an aggressive histologic classification of cervical cancer and the expression of either NF-kB or cyclin D1 (Gynecol Oncol 2012, in revision). In endemic cancers, we found that BCL10 nuclear translocation was closely associated with poor prognosis of advanced oral cancer, pancreatic cancer, breast cancer, and non-small cell lung cancer (NSCLC). Furthermore, in breast and pancreatic cancer cell line, we demonstrated that constitutive activation of BCL10 nuclear translocation-signaling transduction pathway may promote the survival and proliferation of these cancer cells through the increasing expression of NF-kB-dependent genes and a subset of pro-survival genes.Hypothesis: Given the molecular linkage that directs both BCL10 overexpression and nuclear translocation in response to inflammation-related NF-kB signaling pathway, we hypothesized that up-regulation of NF-kB by BCL10 may contribute, in cases of solid tumors, to the malignant transformation of tumor cell growth and to the promotion of tumor progression. To prove this, we will investigate whether BCL10 nuclear translocation and its-associated signaling and transcriptional genes possesses clinical significance in relation to these tumors.Our specific Aims:1.Clarification of the role of BCL10 nuclear expression in the biologic significance and molecular pathogenesis of endemic cancer (breast cancer, NSCLC, pancreatic cancer, and cervical cancer).2.Investigation of BCL10 phosphorylation site, BCL10-associated nuclear protein, and BCL10-transcriptional effect of BCL10 nuclear translocation, and further clarification of signaling pathway and biologic significance of BCL10 nuclear translocation. 3.Further clarification of BCL10 nuclear translocation in the molecular pathogenesis of drug-resistance and radioresistance in endemic cancer, and modulation of BCL10-signaling pathway and BCL10-targeted genes in the treatment of BCL10-overexpressing endemic tumor.Major anticipated achievements: These findings will (1) provide new insights into the moleculobiologic significance of BCL10 nuclear expression in these endemic cancers (2) develop novel treatment strategies for these tumors harboring BCL10 nuclear expression.BCL10NF-kappaB藥物抗藥性放射線抵抗性常見癌症BCL10NF-kappaBChemoresistanceRadioresistanceEndemic cancer