本文選題：順鉑 + Par-4　； 參考：《第三軍醫(yī)大學(xué)》2016年博士論文

【摘要】：研究背景與目的胰腺癌(Pancreatic cancer,PC),是發(fā)生在胰腺的惡性腫瘤。是我們肝膽外科的常見腫瘤。由于早期的胰腺癌沒有明顯癥狀,通常確診的病人都是晚期患者。大約90%的患者就診時(shí),已經(jīng)無法進(jìn)行根治性的手術(shù)治療。統(tǒng)籌整個(gè)患者群體,五年生存率低于5%。大部分患者只能選擇化療作為治療手段。傳統(tǒng)的化學(xué)藥物對(duì)于胰腺癌的控制幾乎沒有什么作用。過去常用藥物5-氟尿嘧啶(5‘-Fluorouracil,5-FU),對(duì)胰腺癌的反應(yīng)率也很少超過25%�，F(xiàn)在,胰腺癌的第一線標(biāo)準(zhǔn)治療仍然是單一使用吉西他濱來化療,其劑量建議1000 mg/m2。但吉西他濱的反應(yīng)率并不突出,也不能完全治愈胰腺癌,吉西他濱的影響有限,只能稍微提升生活品質(zhì),它對(duì)正常細(xì)胞毒性較小,能夠減輕疼痛,稍稍延長患者生命。目前,對(duì)胰腺癌沒有非常有效的抗癌藥品可供選擇,吉西他濱在1998年被美國食品藥物管理局(Food and Drug Administration,FDA)核準(zhǔn)為用于治療胰腺癌的第一個(gè)化療藥品。2005年11月,美國食品藥物管理局核準(zhǔn)了靶向治療藥物埃羅替尼(Erlotinib,即特羅凱)可聯(lián)合吉西他濱合使用,作為胰腺癌的一線化療手段。聯(lián)合使用在存活期及反應(yīng)率比較上有統(tǒng)計(jì)學(xué)意義,但是臨床治療上并不能發(fā)現(xiàn)其帶來的明顯好處。順鉑(cisplatin,CDDP)是經(jīng)典的化療藥物,因?yàn)橐认侔┖苋菀装l(fā)生順鉑耐藥,故沒有用在胰腺癌化療上。而胰腺癌順鉑耐藥機(jī)制,目前尚不清楚。上皮間質(zhì)轉(zhuǎn)化(Epithelial mesenchymal transition,EMT)是細(xì)胞由原來的上皮形態(tài),通過一些反應(yīng),向間充質(zhì)形態(tài)轉(zhuǎn)化,獲得間充質(zhì)細(xì)胞表型的過程。最近越來越多的文獻(xiàn)報(bào)道顯示,激活EMT會(huì)使大部分上皮來源的中路細(xì)胞獲得間質(zhì)表型。EMT過程與腫瘤細(xì)胞的遠(yuǎn)處轉(zhuǎn)移,復(fù)發(fā),腫瘤細(xì)胞侵襲轉(zhuǎn)移力增加密切相關(guān)。還有證據(jù)顯示,激發(fā)EMT過程與腫瘤的化療耐藥密切相關(guān)。在腫瘤細(xì)胞中,EMT的激發(fā)依賴多種信號(hào)傳導(dǎo)途徑的調(diào)控。在胰腺癌中,Zeb-1和其他EMT的調(diào)控子可能維持了胰腺癌的化療耐藥狀態(tài),這說明在胰腺癌中,EMT與化療耐藥密切相關(guān)。因此研究EMT關(guān)鍵分子的調(diào)控機(jī)制、研究胰腺癌細(xì)胞的耐藥機(jī)理,發(fā)展有效的治療措施措施、探索潛在的治療靶點(diǎn),逆轉(zhuǎn)耐藥機(jī)制,有重要意義。前列腺凋亡反應(yīng)蛋白-4(Prostate apoptosis response-4,Par-4),最早被發(fā)現(xiàn)在前列腺癌細(xì)胞中,是一個(gè)促凋亡反應(yīng)蛋白。它是PAR4基因的表達(dá)產(chǎn)物。Par-4蛋白具有獨(dú)特的促腫瘤細(xì)胞凋亡,卻不影響正常細(xì)胞的作用,這使得Par-4蛋白的安全性非常高。再者,Par-4蛋白可以從內(nèi)源性和外源性兩種途徑誘導(dǎo)腫瘤細(xì)胞的凋亡,這讓它的抗腫瘤能力成倍上升。Par-4在一系列的人類癌癥組織中都被發(fā)現(xiàn)下調(diào)包括胰腺癌,它的下調(diào)被認(rèn)為是腫瘤發(fā)生的關(guān)鍵事件之一,而且在胰腺癌的細(xì)胞中,Par-4蛋白的低表達(dá)預(yù)示著非常差的預(yù)后。Par-4蛋白僅憑自身就可誘導(dǎo)腫瘤細(xì)胞的凋亡反應(yīng),而且還可通過增加腫瘤細(xì)胞對(duì)凋亡介質(zhì)的敏感性,如阿霉素、TNF-α(tumor necrosis factor-α),TNF相關(guān)的凋亡反應(yīng)配體,來觸發(fā)腫瘤細(xì)胞凋亡反應(yīng)。研究還顯示,結(jié)腸癌細(xì)胞對(duì)5-FU的敏感性可被Par-4增加。特別是在胰腺癌細(xì)胞中,Par-4在調(diào)節(jié)Bcl-2家族蛋白的小分子阻斷劑導(dǎo)致的胰腺癌細(xì)胞凋亡事件中,扮演著調(diào)節(jié)敏感性的重要角色。近年來,Par-4已經(jīng)被作為一個(gè)非常重要的靶向治療的位點(diǎn),許多臨床試驗(yàn)也已經(jīng)開展。但是,Par-4的下調(diào)是否與胰腺癌的順鉑耐藥有關(guān),到底怎樣參與了耐藥過程,還沒有相關(guān)研究。我們猜測耐順鉑的胰腺癌細(xì)胞中發(fā)生了EMT,Par-4蛋白水平更低。下面來探討CDDP耐藥的胰腺癌細(xì)胞的作用機(jī)制。材料方法及結(jié)果1、以CDDP誘導(dǎo)建立胰腺癌耐藥細(xì)胞株BXPC-3/CDDP。以西南醫(yī)院肝膽實(shí)驗(yàn)室的BXPC-3細(xì)胞為親本細(xì)胞,培養(yǎng)液中CDDP濃度從0.1μg/ml開始,濃度逐漸升至1μg/ml。建成BXPC-3/CDDP耐藥細(xì)胞株。與BXPC-3細(xì)胞相比,BXPC-3/CDDP細(xì)胞更為細(xì)長,細(xì)胞較分散,呈間充質(zhì)細(xì)胞樣形態(tài)改變。MTT實(shí)驗(yàn)檢測細(xì)胞耐藥性。結(jié)果顯示BXPC-3/CDDP細(xì)胞較其親本細(xì)胞BXPC-3明顯耐藥。BXPC-3的耐順鉑細(xì)胞株BXPC-3/CDDP建立成功。以上結(jié)果說明用成功用CDDP濃度梯度法誘導(dǎo)BXPC-3變?yōu)锽XPC-3/CDDP。2、探索耐藥細(xì)胞株BXPC-3/CDDP與EMT的關(guān)聯(lián)。用western blot檢測BXPC-3和BXPC-3/CDDP中EMT標(biāo)志物:snail,twist,E-cadherin,N-cadherin,并作出比較。細(xì)胞Transwell侵襲實(shí)驗(yàn)評(píng)價(jià)其與親本細(xì)胞侵襲轉(zhuǎn)移能力。結(jié)果顯示,相比BXPC-3細(xì)胞,BXPC-3/CDDP細(xì)胞中snail表達(dá)水平上升,twist1表達(dá)水平上升,E-cadherin水平下降,N-cadherin水平上升。Transwell實(shí)驗(yàn)顯示:BXPC-3/CDDP較其親本細(xì)胞BXPC-3侵襲力上升。在BXPC-3/CDDP中,較其親本細(xì)胞BXPC-3,發(fā)生了EMT。以上結(jié)果說明:BXPC-3/CDDP,較其親本細(xì)胞BXPC-3,發(fā)生了EMT改變。3、探索耐藥細(xì)胞株BXPC-3/CDDP中Par-4在mRNA和蛋白水平表達(dá)的情況。Western blot檢測耐藥細(xì)胞株BXPC-3/CDDP中Par-4蛋白表達(dá)水平,RT-PCR檢測耐藥細(xì)胞株BXPC-3/CDDP中Par-4 mRNA水平。以上結(jié)果顯示,較BXPC-3,BXPC-3/CDDP中Par-4在蛋白和mRNA水平均降低了。4、Par-4的過表達(dá)與BXPC-3/CDDP細(xì)胞的順鉑耐藥性、EMT有關(guān)。5、在BXPC-3/CDDP中采用過表達(dá)Par-4策略,用慢病毒包裝轉(zhuǎn)染pcDNA3.1-Par-4后,EMT相關(guān)標(biāo)志物E-cadherin,N-cadherin用western blot檢測。腫瘤細(xì)胞Transwell侵襲試驗(yàn)用來檢測其轉(zhuǎn)染后與未轉(zhuǎn)染的侵襲力對(duì)比。MTT試驗(yàn)檢測耐藥性。結(jié)果顯示,在BXPC-3/CDDP中過表達(dá)Par-4后,E-cadherin水平上升,N-cadherin水平下降。細(xì)胞侵襲轉(zhuǎn)移水平下降,耐藥性降低。呈MET改變。以上結(jié)果顯示在BXPC-3/CDDP中從基因?qū)用嫔险{(diào)PAR4,會(huì)使腫瘤細(xì)胞發(fā)生MET改變,耐藥能力下降。6、干擾BXPC-3中PAR-4基因后,細(xì)胞上皮表型發(fā)生改變。在BXPC-3中采用RNA干擾策略,降低Par-4表達(dá)。轉(zhuǎn)染Par-4 SiRNA(small interfering RNA,小干擾RNA)后,western blot檢測EMT相關(guān)標(biāo)志物E-cadherin,N-cadherin。腫瘤細(xì)胞Transwell侵襲試驗(yàn)用來檢測干擾前后侵襲力對(duì)比。用MTT試驗(yàn)來檢測干擾前后細(xì)胞耐藥性。結(jié)果顯示,在BXPC-3中敲除Par-4后,E-cadherin水平下降,N-cadherin水平上升。細(xì)胞侵襲轉(zhuǎn)移水平上升,耐藥性增高。呈EMT改變。以上結(jié)果證明從基因?qū)用嫦抡{(diào)BXPC-3中PAR-4基因后,腫瘤細(xì)胞發(fā)生了EMT趨勢,耐藥性增加,侵襲轉(zhuǎn)移能力增強(qiáng)。7、BXPC-3中PAR-4基因下調(diào)后,細(xì)胞發(fā)生的EMT與PI3K/Akt(phosphatidylinositol 3-kinase,磷脂酰肌醇3激酶)信號(hào)通路有關(guān)。在BXPC-3中采用RNA干擾策略。轉(zhuǎn)染Par-4 Si RNA后,加入PI3K/Akt阻斷劑LY294002來阻斷該信號(hào)通路。EMT相關(guān)標(biāo)志物E-cadherin,N-cadherin用western blot來檢測。腫瘤細(xì)胞Transwell侵襲試驗(yàn)用來檢測加阻斷劑前后侵襲力對(duì)比。用MTT試驗(yàn)來檢測加阻斷劑前后腫瘤細(xì)胞耐藥性。結(jié)果顯示,在BXPC-3中敲除Par-4,加入PI3K/Akt阻斷劑LY294002后,E-cadherin水平較未加阻斷劑組上升,N-cadherin水平較未加阻斷劑組下降。細(xì)胞侵襲轉(zhuǎn)移水平較未加阻斷劑組下降,耐藥性降低。EMT改變被阻斷。另一試驗(yàn)證實(shí),BXPC-3轉(zhuǎn)染Par-4 siRNA后隨時(shí)間推移測western測p Akt/total Akt比值,呈逐漸上升趨勢。以上結(jié)果表明基因?qū)用鍼AR4的下調(diào)通過PI3K/Akt途徑激活了EMT,導(dǎo)致了BXPC-3細(xì)胞順鉑耐藥。8、腫瘤細(xì)胞裸鼠移植瘤實(shí)驗(yàn)。接種腫瘤細(xì)胞后,用順鉑腹腔注射治療,測各組腫瘤體積變化與70天生存率。結(jié)果示:順鉑對(duì)Par-4 siRNA-transfected BXPC-3組幾乎沒有作用,但加入PI3K/Akt阻滯劑LY294002后,該組的順鉑耐藥被逆轉(zhuǎn)。以上解說表明,在體外實(shí)驗(yàn)中,阻斷PI3K/Akt途徑可以逆轉(zhuǎn)Par-4下調(diào)引起的EMT介導(dǎo)的耐藥。研究結(jié)論本研究明確了耐順鉑的胰腺癌細(xì)胞BXPC-3/CDDP中,腫瘤細(xì)胞發(fā)生了EMT改變。同時(shí),其Par-4在蛋白和mRNA水平都被發(fā)現(xiàn)下降。在基因?qū)用嫔险{(diào)耐藥細(xì)胞株BXPC-3/CDDP的PAR-4水平,可以逆轉(zhuǎn)順鉑耐藥,通過MET(mesenchymal epithelial transition)途徑。
[Abstract]:Background and objective Pancreatic cancer (PC) is a malignant tumor occurring in the pancreas. It is a common tumor in our department of hepatobiliary surgery. Since early pancreatic cancer has no obvious symptoms, the patients who are usually diagnosed are late patients. About 90% of the patients have been unable to perform radical surgical treatment. The five year survival rate is less than 5%. most patients can only choose chemotherapy as a treatment. Traditional chemical drugs have little effect on the control of pancreatic cancer. 5- fluorouracil (-Fluorouracil, 5-FU) was used in the past, and the response rate of pancreatic cancer was rarely over 25%.. The first line of standard treatment for pancreatic cancer is still A single use of gemcitabine chemotherapy, the dosage recommended 1000 mg/m2., but the response rate of gemcitabine is not prominent, and can not completely cure pancreatic cancer. The effect of gemcitabine is limited, only slightly improve the quality of life, it is less toxic to normal cells, can reduce pain, and slightly prolong the patient's life. At present, there is no very good for pancreatic cancer. The effective anticancer drug was selected. In 1998, gemcitabine was approved by the Food and Drug Administration (FDA) as the first chemotherapeutic drug for the treatment of pancreatic cancer in November. The US Food and Drug Administration approved the combination of the target therapy drug, erlotinib (Erlotinib, special Luo Kai), and gemcitabine combined with gemcitabine. Use, as a first-line chemotherapy for pancreatic cancer. Combined use is statistically significant in survival and response rates, but clinical treatment does not find its obvious benefits. Cisplatin (CDDP) is a classic chemotherapeutic agent because pancreatic cancer is very susceptible to cisplatin resistance, so it is not used in pancreatic cancer chemotherapy. The mechanism of cisplatin resistance in adenocarcinoma is not clear. Epithelial mesenchymal transition (EMT) is the process of cell transformation from the original epithelium to mesenchyme phenotype through some reactions. More and more recent reports suggest that activation of EMT will lead to most of the epithelial sources. The process of obtaining interstitial phenotypic.EMT from the path cells is closely related to distant metastasis, recurrence, and invasion and metastasis of tumor cells. There is also evidence that the activation of the EMT process is closely related to the chemotherapeutic resistance of the tumor. In the tumor cells, the excitation of EMT depends on the regulation of a variety of signal transduction pathways. In pancreatic cancer, Zeb-1 and other EMT are in the pancreatic cancer. The regulator may maintain the chemotherapeutic resistance of pancreatic cancer, which indicates that EMT is closely related to chemotherapy resistance in pancreatic cancer. Therefore, it is of great significance to study the regulatory mechanism of the key molecules of EMT, to study the mechanism of the drug resistance of pancreatic cancer cells, to develop effective treatment measures, to explore potential therapeutic targets and to reverse the mechanism of drug resistance. Apoptosis reactive protein -4 (Prostate apoptosis response-4, Par-4), the earliest found in prostate cancer cells, is a proapoptotic reaction protein. It is the expression product of the PAR4 gene,.Par-4 protein, which has a unique tumor promoting cell apoptosis, but does not affect the function of normal cells, which makes Par-4 protein safe. And Par-4, Par-4. The protein can induce apoptosis of tumor cells from two endogenous and exogenous pathways, which makes its antitumor capacity multiplied by.Par-4 in a series of human cancer tissues, which are found to be down-regulated, including pancreatic cancer. Its downregulation is considered to be one of the key events of the tumor, and the low Par-4 protein in the cells of pancreatic cancer. The expression indicates a very poor prognosis,.Par-4 protein can induce apoptosis response only by itself, and can also trigger the apoptosis response of tumor cells by increasing the sensitivity of tumor cells to the apoptosis medium, such as adriamycin, TNF- alpha (tumor necrosis factor- a) and TNF related apoptosis reaction ligands. The sensitivity of cells to 5-FU can be increased by Par-4. Especially in pancreatic cancer cells, Par-4 plays an important role in regulating the apoptosis of pancreatic cancer cells caused by the small molecular blockers of the Bcl-2 family protein. In recent years, Par-4 has been used as a very important target therapy site, many clinical trials It has also been carried out. However, whether the down-regulation of Par-4 is associated with cisplatin resistance in pancreatic cancer and how to participate in the drug resistance process, there is no related study. We speculate that EMT and Par-4 protein levels have occurred in pancreatic cancer cells resistant to cisplatin. The mechanism of action of CDDP resistant pancreatic cancer cells is discussed below. Material methods and results are 1, CD DP induced the establishment of pancreatic cancer resistant cell line BXPC-3/CDDP. with BXPC-3 cells in the liver and gallbladder Laboratory of Southwest Hospital as parental cells. The concentration of CDDP in the culture medium started from 0.1 mu g/ml, and the concentration gradually increased to 1 g/ml. to build the BXPC-3/CDDP resistant cell lines. Compared with BXPC-3 cells, the BXPC-3/CDDP cells were more slender, and the cells were more dispersed and mesenchyme cells. The results showed that BXPC-3/CDDP cells were more successful than the BXPC-3 resistant cisplatin resistant.BXPC-3 cell line BXPC-3/CDDP, which was significantly more resistant to BXPC-3. The results showed that BXPC-3 became BXPC-3/CDDP.2 with the CDDP concentration gradient method successfully, and the association between BXPC-3/CDDP and EMT was explored. Tern blot detected the EMT markers in BXPC-3 and BXPC-3/CDDP: snail, twist, E-cadherin, N-cadherin, and made a comparison. Cell Transwell invasion test evaluated the invasion and metastasis of parental cells. The dherin level rising.Transwell experiment showed that BXPC-3/CDDP was more aggressive than its parent cell BXPC-3. In BXPC-3/CDDP, the result of EMT. above the parent cell BXPC-3 showed that BXPC-3/CDDP, compared with the parent cell BXPC-3, occurred EMT change.3, and explored the expression of the protein level in the resistant fine cell BXPC-3/CDDP. The expression level of Par-4 protein in drug resistant cell line BXPC-3/CDDP was detected by.Western blot, and RT-PCR was used to detect the level of Par-4 mRNA in the drug-resistant cell line BXPC-3/CDDP. P was used to express the Par-4 strategy. After the transfection of pcDNA3.1-Par-4 with lentivirus package, the EMT related marker E-cadherin and N-cadherin were detected by Western blot. The tumor cell Transwell invasion test was used to detect the resistance of the transfected and untransfected invasive.MTT test to detect the resistance. The results showed that the Par-4 was over expressed in BXPC-3/CDDP. The level of dherin increased and the level of N-cadherin decreased. The level of cell invasion and metastasis decreased and the drug resistance decreased. The results showed that the up-regulation of PAR4 from the gene level in BXPC-3/CDDP could cause the MET change of the tumor cells and the decrease of resistance to.6. The epithelial phenotype changes after the interference of PAR-4 gene in BXPC-3. RN in BXPC-3 uses RN. A interference strategy, reducing the expression of Par-4. After transfection of Par-4 SiRNA (small interfering RNA, small interference RNA), Western blot tests EMT related E-cadherin, and the tumor cell invasion test is used to detect the invasion force before and after interference. In addition to Par-4, the level of E-cadherin decreased and the level of N-cadherin increased. The level of cell invasion and metastasis increased and the drug resistance increased. The results showed that after the gene level downregulation of the PAR-4 gene in BXPC-3, the tumor cells had the EMT trend, the resistance increased, the invasion and transfer energy increased.7, and the PAR-4 gene in BXPC-3 was down, and the cell occurred. EMT is related to the signaling pathway of PI3K/Akt (phosphatidylinositol 3-kinase, phosphatidylinositol 3 kinase). RNA interference strategy is used in BXPC-3. After Par-4 Si RNA, PI3K/Akt blocker LY294002 is used to block the signal pathway.EMT related markers. The MTT test was used to detect the resistance of tumor cells before and after the addition of blockers. The results showed that after knocking out Par-4 and adding PI3K/Akt blocker LY294002 in BXPC-3, the level of E-cadherin was higher than that of the non blocking agent group, and the level of N-cadherin was lower than that of the non blocking agent group. The level of cell invasion and metastasis was not the same. With the decrease of the blocker group and the decrease of the resistance to.EMT, the other test confirmed that the P Akt/total Akt ratio measured by BXPC-3 transfection to Par-4 siRNA showed a gradual increase. The above results showed that the downregulation of the gene level PAR4 was activated by PI3K/Akt pathway, leading to the cisplatin resistance of the BXPC-3 cells, the tumor cells. The tumor cells were inoculated in nude mice. After inoculation of tumor cells, cisplatin was intraperitoneally injected to test the changes of tumor volume and 70 natural survival rate. The results showed that cisplatin had little effect on Par-4 siRNA-transfected BXPC-3 group, but after the addition of PI3K/Akt blocker LY294002, the cisplatin resistance of the group was reversed. PI3K/Akt pathway can reverse the EMT mediated resistance induced by Par-4 downregulation. Conclusion this study identified the EMT changes in the tumor cells in the pancreatic cancer cell BXPC-3/CDDP resistant to cisplatin. At the same time, the Par-4 and mRNA levels were found to be reduced. The PAR-4 level of the drug resistant cell line BXPC-3/CDDP was up-regulated at the gene level. Resistance to cisplatin was passed through the MET (mesenchymal epithelial transition) pathway.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R735.9

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