【摘要】：盡管實驗研究人員在不斷的了解癌癥的病因?qū)W，并且一直在嘗試開發(fā)新的診斷和治療方法，但是，惡性腫瘤的發(fā)病率和死亡率的仍然沒有得到有效的控制。造成這種情況的其中一個主要原因是患者化療后，仍然沒有行之有效的辦法來抑制部分耐藥腫瘤的復(fù)發(fā)。對化療的耐藥性可能是先天存在的，即從治療開始之前便存在的，也可能是在治療的過程中逐漸產(chǎn)生的，這是一種變化的情況。舉例來說，幾乎與化療治療的所有非小細胞肺癌患者最終都會發(fā)展為抗癌藥物耐受�；熕幬锏纳飳W(xué)機制是十分復(fù)雜的，通常包括以下一種或多種機制：抑制細胞凋亡，誘導(dǎo)并且抑制的DNA修復(fù)機制，變更藥物靶標的結(jié)構(gòu)，修改細胞膜的成分或者結(jié)構(gòu)（從而降低了藥物的吸收)，以及藥物的外排。關(guān)于后者，一個主要的問題是交叉耐藥性，其中涉及廣譜藥物因為癌細胞膜中存在的轉(zhuǎn)運蛋白產(chǎn)生的耐藥性，這不僅是針對單一活性藥物或化學(xué)相關(guān)藥物，患者體內(nèi)耐藥蛋白的表達會增加，而且對于全身性癥狀的化療劑，甚至尚未施加過任何化療藥物的患者，都可能產(chǎn)生耐藥的作用。這一現(xiàn)象被稱為多藥耐藥（MDR)，其中參與了這一過程的蛋白質(zhì)稱為MDR蛋白。人們對于多藥耐藥蛋白的研究始于1974年，當時Victor Ling和Larry Thompson闡述了他們的實驗結(jié)果，選取穩(wěn)定的CHO細胞系，成功復(fù)制增殖了對秋水仙素耐藥的細胞，并且發(fā)現(xiàn)耐藥細胞并沒有讓秋水仙堿進入細胞質(zhì)。研究人員還發(fā)現(xiàn)這種細胞也能夠抗地美可辛，放線菌素D和長春堿。有人進一步指出，對秋水仙堿攝取敏感的細胞，參與到細胞分子轉(zhuǎn)運過程是被動的，耐藥細胞則是經(jīng)歷一個主動的過程，原因是耐藥細胞可能被氰化物，疊氮化鈉和二硝基苯酚等多種化合物抑制。據(jù)進一步實驗結(jié)果證明，未成熟細胞和抗性細胞之間的主要區(qū)別是一個170kDa的質(zhì)膜糖蛋白是否表達，這個蛋白被稱為P-糖蛋白。P-糖蛋白也被稱為P-gp、 ABCB1或MDR1。它能夠在很短的時間內(nèi)大量的產(chǎn)生，P糖蛋白與其他的膜轉(zhuǎn)運蛋白有所不同，它參與多藥耐藥機制。舉例來說，在1990年，有人描述了MCF-7/AdrVp耐藥細胞株中含有蒽環(huán)類95kDa的膜蛋白，這個蛋白后來被稱為BCRP (乳腺癌耐藥蛋白,又名ABCG2)。在1992年，Cole和其他合作研究人員發(fā)現(xiàn)并克隆另一個磷酸糖蛋白，這種酶在阿霉素耐藥細胞株H69AR中過度表達，人們將這種蛋白命名為MRP (也稱為多藥耐藥相關(guān)蛋白）。在之后的不久，研究人員明確指出，所有這些蛋白質(zhì)均含有一些相同的基因序列和發(fā)揮同源性的功能，并且均被定義為ATP結(jié)合蛋白超家族(ATP-binding cassette superfamily,ABCs)的成員。ATP結(jié)合蛋白超家族是最大的跨膜蛋白家族，根據(jù)序列和同源性，分為A到G七個亞型。 ABCC家族成員主要由大約200個氨基酸構(gòu)成，這種獨特的氨基酸跨膜結(jié)構(gòu)把ABCC家族成員與其他的ABC成員區(qū)分開來。ABCC4是ABC轉(zhuǎn)運C亞家族的成員。ABC轉(zhuǎn)運蛋白主要是跨膜蛋白，能夠介導(dǎo)ATP-依賴的細胞通路運轉(zhuǎn)其他分子物質(zhì)穿過細胞膜。ABCC4基因位于人染色體13q32.1位點，在ABCC4基因編碼后表達的蛋白質(zhì)是ABCC/MRP家族中長度最短的成員，其作用是介導(dǎo)各種外源性和內(nèi)源性分子的流出。 在對ABCC4基因敲除小鼠的實驗研究顯示，ABCC4具有重要的生理作用，特別是作用在肝臟，腦組織，和腎臟。在膽汁淤積性損傷的病例中，膽汁通過肝臟時受阻，在大鼠和小鼠膽管結(jié)扎后，會出現(xiàn)ABCC4上調(diào)，并且驗證在患者中也存在進行性的家族性肝內(nèi)膽汁淤積。ABCC4介導(dǎo)發(fā)生的谷胱甘肽-依賴性膽汁酸外排，在特定條件下的這種誘導(dǎo)是一種保護性反應(yīng)，作用是防止肝壞死。除了清除代謝產(chǎn)物，ABCC4能夠通過外排活性藥物，以抵抗各種外來物質(zhì)可能對重要組織造成的損傷。ABCC4缺陷的小鼠對多種藥物（抗癌藥拓撲替康，抗病毒藥物阿德福韋和替諾福韋）表現(xiàn)出腎臟排泄功能降低。相應(yīng)的，在血漿和某些組織中檢測到托泊替康的水平升高。ABCC4缺乏也使得拓撲替康能夠穿過血腦屏障，進而滲透到中樞神經(jīng)系統(tǒng)和腦。此外， ABCC4基因敲除小鼠與野生型同窩小鼠相比，基因敲除小鼠在骨髓，胸腺，脾臟和腸中都增強了抗病毒藥物的吸收。另外已經(jīng)有實驗研究表明，ABCC4在髓系祖細胞中高度表達，通過主動外排機制，以保護這些細胞免受硫嘌呤誘導(dǎo)產(chǎn)生的造血毒性。 對于直腸癌的預(yù)后評判，目前公認的判斷方法是TNM分期，細胞分化程度，區(qū)域淋巴結(jié)及血清腫瘤標志物的表達，這些指標均與直腸癌的長期預(yù)后相關(guān)。.然而，對LARC患者的術(shù)前放療短期效果驗證和長期預(yù)后效果檢測，到目前為止被證明是金標準的生物活性標記物還很少。目前比較新型的輔助治療模型是，對局部晚期直腸癌患者的治療是結(jié)合了5-FU為基礎(chǔ)的化學(xué)療法和其他的放射療法。因此，在使用ABCC4作為一種新型的生物標記物在預(yù)測LARC患者抗輻射能力的最大優(yōu)點在于，這個比較理想的分子標記同時與照射和細胞毒性藥物都具有相關(guān)聯(lián)意義。ABCC4的耐藥相關(guān)性在一些研究中已經(jīng)報道了，其中涉及到多種癌細胞類型（包含直腸癌）�？傊�，這些研究突出表明ABCC4作為轉(zhuǎn)運體能夠發(fā)揮多個功能，保護生命器官，防止生物代謝物的積累，防止化療藥物的損傷。 本實驗首先采用細胞增殖實驗，在五株直腸癌細胞系中挑選出放療敏感株LOVO和抗性株RKO，然后用免疫組化的方法，觀察了敏感株LOVO細胞和抗性株RKO細胞中ABCC4表達的情況，結(jié)果顯示，僅能在細胞膜和細胞質(zhì)中觀察到染色顆粒，在細胞核中看不到ABCC4的棕黃色染色顆粒。這個實驗結(jié)果與國外研究人員在其他腫瘤細胞系中觀察到的結(jié)果是一致的（Zaman以及他的同事在肺癌細胞中做過相應(yīng)的驗證），更進一步的實驗結(jié)果是，敏感株LOVO細胞，其ABCC4的高表達率為17%，而放射抵抗株RKO細胞的高表達率為71%，敏感株細胞明顯低于抵抗株細胞，差異具有統(tǒng)計學(xué)意義。這個結(jié)果說明，ABCC4的高表達很可能參與到放射抵抗的生物學(xué)分子通路中。Havie等人在前期的研究文獻中已經(jīng)指明，ABCC4在T淋巴細胞白血病細胞中也具有高表達的情況，同時這種細胞也會產(chǎn)生放療抗性。作者還指出，在接受放療失敗后，即使使用化學(xué)療法的手段，耐藥性依然沒有消失。隨后，展開更深入的研究，對總計93例患者接受經(jīng)腹前切除術(shù)，28例患者接受腹會陰聯(lián)合切除術(shù)的治療手段。根據(jù)術(shù)后病理報告判斷環(huán)周切緣均為陰性。術(shù)后中位隨訪時間34.5個月(SD=8.6)。與預(yù)后相關(guān)的臨床病理多因素進行分析。Cox風險分析顯示ABCC4高表達(P=.036)、p53突變型(P=.047)、病理反應(yīng)差(P=.044)的患者預(yù)后不良，3年總生存率低；ABCC4高表達(P=.027)、p53突變型(P=.019)、最終病理分期差(P=.032)的患者預(yù)后不良，3年無病生存率相對較低。慢病毒轉(zhuǎn)染獲得穩(wěn)定下調(diào)ABCC4蛋白的細胞株。Real-time PCR以及Western Blot結(jié)果均證實，其在RKO-KD、HT29-KD細胞中持續(xù)有效抑制abcc4基因表達，為后續(xù)細胞功能實驗提供一定的理論基礎(chǔ)，可以繼續(xù)分子機制研究方面的探索。Real-time PCR結(jié)果顯示abcc4mRNA在HT29-KD組的表達量(0.20±0.02)明顯少于HT29-NC組(0.99±0.02)和HT29-CON組(0.98±0.03)(P 0.05)；Western Blot實驗表明ABCC4蛋白表達水平在HT29-KD組(0.25±0.02)顯著低于HT29-NC組(0.98±0.02)和HT29-CON組(0.98±0.03)(P 0.05)。而在陰性對照組HT29-NC和空白對照組HT29-CON之間比較，兩者之間均無顯著差異(P0.05)。通過測量腫瘤直徑計算的方法，我們發(fā)現(xiàn)，與對照組相比，放療后RKO-KD裸鼠移植瘤模型腫瘤生長狀態(tài)呈現(xiàn)時間依賴性顯著抑制(P .05)，觀察終點測量平均腫瘤重量，RKO-KD組瘤重2.01克(±0.18)明顯輕于RKO-NC組3.97克(±0.21)以及RKO-CON組4.01克(±0.19)(P .05)。在三組的空白對照組當中，裸鼠的腫瘤體積大小與重量均無統(tǒng)計學(xué)顯著差異(P.05)。4Gy劑量射線照射后，細胞內(nèi)cAMP含量迅速上升后，呈現(xiàn)時間依賴性減少。。平均cAMP濃度在RKO-KD組0.66(±0.25)%比RKO-NC組0.45(±0.15)%和RKO-CON組0.46(±0.16)%顯著升高(P .05)。同樣處理后的細胞檢測細胞周期分布，RKO-KD組細胞43.54(±3.07)%處于G0/G1期的比例明顯少于RKO-NC組細胞65.73(±3.78)%以及RKO-CON組細胞66.52(±3.64)%(P .05)，表明在RKO-KD組細胞喪失G1-S監(jiān)測點DNA修復(fù)能力，進入相對放療敏感的G2期從而易于遭受輻射損傷。在未經(jīng)照射的三組空白對照中，實驗結(jié)果顯示，分析細胞周期分布情況，無統(tǒng)計學(xué)意義上的顯著性差異(P.05)。 這里值得強調(diào)的是，耐藥的分子機制與輻射抗性之間有很大的不同。細胞毒性藥物是發(fā)揮一種持續(xù)的，緩慢的和系統(tǒng)性的生物化學(xué)作用，因此對于在細胞凋亡信號通路的關(guān)鍵蛋白，這些蛋白具有足夠的時間做出改變，，對藥物進行應(yīng)答，這可能很好地解釋化療耐藥的潛在機制，然而，由于照射的方式，是給機體直接提供了一個瞬時高能量并且直達癌細胞內(nèi)部，通過產(chǎn)生的活性氧誘導(dǎo)DNA的大規(guī)模損傷。細胞凋亡信號通路可能不是最主要的決定因素。在此，我們確定了下調(diào)ABCC4表達，在射線輻照后，會提高細胞內(nèi)cAMP濃度積累，細胞周期G1-S期檢查點明顯不足，這可能解釋了其中的機制，幫助闡明抑制ABCC4的shRNA表達后，會誘導(dǎo)促進大腸癌細胞凋亡。 總之，目前的實驗研究表明，ABCC4是體內(nèi)實驗和體外實驗中，都表現(xiàn)出對射線輻照的調(diào)節(jié)作用，是極其重要的敏感分子，并與局部侵襲性直腸癌同時接收術(shù)前放療患者的不良預(yù)后有顯著相關(guān)。這些分析數(shù)據(jù)支持以下理論，ABCC4可以看成是一個有用的預(yù)測指標或者靶點，對于局部侵襲性直腸癌患者是否應(yīng)該接受術(shù)前放療，和預(yù)后的情況評估有一定的指導(dǎo)意義。提示未來可以更加深入的研究，明確ABCC4在治療前篩查的臨床意義，為提高預(yù)后，改善患者生活質(zhì)量提供了新的思路。
[Abstract]:Although the researchers are constantly learning the etiology of cancer and have been trying to develop new methods of diagnosis and treatment, the incidence and mortality of malignant tumors are still not effectively controlled. One of the main reasons for this is that the patients are still not effective after chemotherapy. The relapse of some drug-resistant tumors. The resistance to chemotherapy may be innate, that is, before the treatment begins and may also be produced in the process of treatment. This is a change. For example, almost all patients with non small cell lung cancer treated with chemotherapy will eventually develop to anticancer drug tolerance. The biological mechanism of chemotherapeutic drugs is very complex, usually including one or more mechanisms: inhibiting apoptosis, inducing and inhibiting the DNA repair mechanism, changing the structure of the drug target, modifying the composition or structure of the cell membrane (and reducing the absorption of drugs), as well as the efflux of the drug. A major question about the latter The problem is cross resistance, which involves the resistance of broad-spectrum drugs to transporters in the membrane of cancer cells, not only for single active drugs or chemical related drugs, but also in the expression of drug resistant proteins in the patient's body, and for patients with systemic symptoms, or even those who have not had any chemotherapy drugs. This phenomenon is known as multidrug resistance (MDR), and the protein involved in this process is called MDR protein. The study of multidrug resistant proteins began in 1974, when Victor Ling and Larry Thompson elaborated their experimental results, selected a stable CHO cell line, and successfully replicated and proliferated to autumn. Narcissuin resistant cells and found that drug-resistant cells did not allow colchicine to enter cytoplasm. The researchers also found that the cells were also able to resist actinomycin, actinomycin D and Changchun base. One active process is that resistant cells may be inhibited by a variety of compounds such as cyanide, sodium azide, and two nitrophenol. According to further experimental results, the main difference between the immature and resistant cells is whether a 170kDa plasma membrane glycoprotein is expressed, and this protein is called the P- glycoprotein.P- glycoprotein. P-gp, ABCB1, or MDR1. can be produced in a very short period of time, and P glycoproteins are different from other membrane transporters. It is involved in multidrug resistance mechanisms. For example, in 1990, a membrane protein containing anthracycline 95kDa was described in MCF-7/AdrVp resistant cell lines, which was later called BCRP (breast cancer resistance). Protein, also known as ABCG2). In 1992, Cole and other cooperative researchers found and cloned another phosphate glycoprotein, which was overexpressed in the doxorubicin resistant cell strain H69AR. People named the protein MRP (also called multidrug resistance associated protein). The ATP binding protein superfamily (ATP-binding cassette superfamily, ABCs), a member of the.ATP binding protein superfamily, is the largest family of transmembrane proteins, which are divided into seven subtypes from A to G according to sequence and homology.
The members of the ABCC family are mainly composed of about 200 amino acids. This unique amino acid transmembrane structure distinguishes ABCC family members from other ABC members..ABCC4 is a member of the ABC transshipment C subfamily,.ABC transporters are mainly transmembrane proteins, and can mediate ATP- dependent cells through other molecular substances through the cell membrane.ABCC4 The gene is located at the 13q32.1 site of the human chromosome. The protein expressed by the ABCC4 gene is the shortest member of the ABCC/MRP family, and its role is to mediate the outflow of a variety of exogenous and endogenous molecules.
The experimental study of ABCC4 gene knockout mice showed that ABCC4 had important physiological functions, especially in the liver, brain tissue, and kidney. In cases of cholestasis, bile was blocked through the liver. After ligation of the bile ducts in rats and mice, the ABCC4 up-regulated and a progressive home was also found in the patients. Human intrahepatic cholestasis.ABCC4 mediated glutathione dependent bile acid efflux, which is a protective reaction under specific conditions, is a protective reaction to prevent liver necrosis. In addition to removing metabolites, ABCC4 can pass out active drugs to resist the possible damage to important tissues by various external substances in.ABCC4 deficiency. The trapped mice showed a decrease in renal excretion by a variety of drugs (antitumor drugs topotecan, antiviral drugs A Duff Vee and Nuo Fuwei). Correspondingly, the elevated levels of.ABCC4 deficiency in plasma and some tissues showed that topotecan was able to penetrate the blood brain barrier and then infiltrate into the central nervous system and the brain. In addition, ABCC4 gene knockout mice have enhanced the absorption of antiviral drugs in bone marrow, thymus, spleen and intestines compared with wild type mice. In addition, experimental studies have shown that ABCC4 is highly expressed in medullary progenitor cells and protects these cells from sulfur purine induced by the active platoon system. Hematopoiesis.
For the prognosis of rectal cancer, TNM staging, cell differentiation, regional lymph nodes and the expression of tumor markers in the region are associated with the long-term prognosis of rectal cancer. However, the short-term effect of preoperative radiotherapy and the long-term prognosis of LARC patients have been proved so far. There are few biomarkers for the gold standard. A new model of adjuvant therapy is the combination of 5-FU based chemotherapy and other radiation therapy for patients with locally advanced rectal cancer. Therefore, the greatest advantage of using ABCC4 as a new biomarker in predicting the radiation resistance of LARC patients is In some studies, this relatively ideal molecular marker associated with both exposure and cytotoxic drugs has been reported in some studies, involving a variety of cancer cell types (including rectal cancer). In conclusion, these studies suggest that ABCC4 can play multiple functions and protect life as a transporter. Organs prevent the accumulation of biological metabolites and prevent the damage of chemotherapeutic drugs.
In this experiment, the cell proliferation test was first used to select the radiotherapy sensitive strain LOVO and the resistant strain RKO in five rectal cancer cell lines. Then the expression of ABCC4 in the sensitive LOVO cells and the resistant strain RKO cells was observed by immunohistochemical method. The results showed that the staining particles could be observed only in the cell membrane and cytoplasm, and the nuclei were in the nucleus. The results were consistent with the results observed by foreign researchers in other tumor cell lines (Zaman and his colleagues in lung cancer cells), and further experimental results were that the sensitive strain of LOVO cells, the high expression of ABCC4, was 17%, and radiation resistance was 17%. The high expression rate of RKO cells was 71%, and the sensitive strain cells were significantly lower than those of the resistant strain cells. The results showed that the high expression of ABCC4 was likely to be involved in the biological pathway of radiation resistance, and.Havie et al. In the previous research literature has indicated that ABCC4 is also found in T lymphocyte leukemia cells. The authors also pointed out that, after the failure of the radiotherapy, the drug resistance was still not disappearing even with the means of chemotherapy. Then, a more in-depth study was carried out for the total of 93 patients undergoing pre abdominal excision, and 28 patients received a combination of abdominal perineal resection. The circumferential margin of the circumferential margin was negative according to the postoperative pathological report. The median follow-up time was 34.5 months (SD=8.6). The.Cox risk analysis showed that the high expression of ABCC4 (P=.036), the p53 mutant (P=.047), the pathological response poor (P=.044) patients had poor prognosis, the 3 year total survival rate was low, and the ABCC4 high expression (P=). .027), p53 mutant (P=.019), the final pathological staging (P=.032) patients have poor prognosis, and the 3 year disease free survival rate is relatively low. The lentivirus transfection obtained the stable and down-regulation of the ABCC4 protein cell line.Real-time PCR and Western Blot results all confirmed that the gene expression in RKO-KD and HT29-KD cells continued to effectively inhibit the expression of the ABCC4 gene, for subsequent cell work. .Real-time PCR results showed that the expression of abcc4mRNA in HT29-KD group (0.20 + 0.02) was significantly less than that of HT29-NC group (0.99 + 0.02) and HT29-CON group (0.98 + 0.03) (P 0.05), and Western Blot experiment showed that the expression level of ABCC4 protein was in HT29-KD group (0.25 + 0.02). Significantly lower than group HT29-NC (0.98 + 0.02) and group HT29-CON (0.98 + 0.03) (P 0.05), but there was no significant difference between the negative control group HT29-NC and the blank control group HT29-CON (P0.05). By measuring the tumor diameter calculation method, we found that the tumor growth pattern of the RKO-KD nude mice after radiotherapy was compared with those in the radiotherapy group. The state showed a significant time dependence inhibition (P.05), the average tumor weight was measured at the end point, the tumor weight of the RKO-KD group was 2.01 grams (+ 0.18) significantly lighter than that of the RKO-NC group (3.97 g) and 4.01 grams (0.19) (P.05) in the RKO-CON group. In the blank control group, there was no significant difference between the size and weight of the tumor in the nude mice (P.05).4Gy dose. After the radiation, the intracellular cAMP content increased rapidly and showed a time dependent decrease.. the average cAMP concentration was 0.66 (+ 0.25)% in the RKO-KD group (+ 0.15)% and 0.46 (0.16)% in the RKO-CON group (P.05). The cell cycle distribution of the treated cells and the percentage of 43.54 (+ 3.07)% in RKO-KD group cells were obviously in the G0/G1 stage. Less than 65.73 (+ 3.78)% of cells in group RKO-NC and 66.52 (+ 3.64)% of cells in group RKO-CON (P.05), indicating that the cells lost the ability to repair DNA at the G1-S monitoring point in RKO-KD group, and were easily exposed to radiation damage. In the three blank controls of unirradiated groups, the experimental results showed that the distribution of cell cycle was analyzed and no system was found. Significant difference in the meaning of the study (P.05).
It is worth emphasizing that there is a great difference between the molecular mechanism of drug resistance and the radiation resistance. Cytotoxic drugs play a continuous, slow and systematic biochemical role, so for the key proteins in the apoptotic signaling pathway, these proteins have enough time to make changes and respond to drugs. It may well explain the potential mechanism of chemoresistance, however, as a result of exposure, the body directly provides an instantaneous high energy and directly to the inside of the cancer cells, and induces a massive damage to DNA through the production of reactive oxygen. The apoptotic signaling pathway may not be the most important determinant. Here, we have determined the downregulation of ABCC 4 expression, after radiation, can increase the accumulation of intracellular cAMP concentration, and the cell cycle G1-S phase checkpoint is obviously inadequate, which may explain the mechanism, helping to clarify the inhibition of shRNA expression of ABCC4 and induce the apoptosis of colorectal cancer cells.
In conclusion, the current experimental study shows that ABCC4 is a very important sensitive molecule in both in vivo and in vitro experiments, which is a very important sensitive molecule, and has a significant correlation with the poor prognosis of patients receiving preoperative radiotherapy for local invasive rectal cancer. These data support the following theory that ABCC4 can be considered as a one. A useful predictor or target is of guiding significance for the evaluation of preoperative radiotherapy for local invasive rectal cancer and the evaluation of the prognosis. It is suggested that a more in-depth study should be made in the future to clarify the ABCC4 screening before treatment.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R735.37;R730.55

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