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Molecular Mechanisms of Human 67kDa Laminin Receptor (67LR) in Cell Adhesion Mediated Multidrug Resistance on Colon Cancer Cell Line SW480

Author: LuChunLei
Tutor: ZhangHongWei
School: Fourth Military Medical University
Course: Surgery
Keywords: Colon cancer Adhere to Laminin Cell adhesion mediated drug resistance Apoptosis 67LR siRNA
CLC: R735.3
Type: Master's thesis
Year: 2009
Downloads: 57
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Abstract


The phenomenon of multidrug resistance (multidrug resistance, MDR) is the main reason for failure of chemotherapy. At home and abroad has been found in the cell membrane, cytoplasm and nucleus of MDR-related molecules, and speculated that the molecular mechanism, but does not fully explain the phenomenon of tumor MDR The adhesion of the tumor cells with the extracellular matrix, can lead to drug resistance, and this form of resistance is called cell adhesion mediated drug resistance (Cell adhesion mediated DRUG Resistance, CAM-DR). The study found that the 67kDa laminin receptor (human 67kDa laminin receptor, 67LR) mediated colon cancer cells with extracellular matrix components laminin (laminin, LN) adhesion and tumor closely related to a variety of biological behavior . LN adhesion The aim of this study was to study 67LR mediated colon cancer cells with extracellular matrix components for their drug sensitivity and depth 67LR mechanisms involved in colon cancer CAM-DR molecules as adhesion molecules, and will contribute to an overall understanding of the occurrence of colon cancer MDR and regulatory mechanisms. Objective: To study the adhesion state for a variety of chemotherapy drug was well tolerated, and explore its mechanisms of resistance; the 67LR expression downward colon cancer cell subline model and its specific ligand, 67LR LN colon cancer cell line SW480 state-mediated adhesion of SW480 cells to recognize each other, in-depth to explore the 67LR functionality and molecular mechanisms mediated colon cancer cell CAM-DR will contribute to a comprehensive understanding of the occurrence of colon cancer MDR and regulatory mechanisms. Methods: the first part: 1. Experimental studies of colon cancer cell line SW480 cell extracellular matrix cell adhesion LN and negative control component of an important component of bovine serum albumin (BSA) adhesion ability differences; 2 detected by MTT assay adhesion the LN and BSA colon cancer cell line SW480 chemotherapy drug 5 - fluorouracil (5-Fu) and cisplatin (DDP) drug sensitivity; detected by means of flow cytometry (FCM) adhesion on LN and BSA SW480 cells doxorubicin accumulation and retention, and to calculate the corresponding pump drugs out rate; detected by Annexin V / PI staining adhesion to LN and BSA colon cancer cell line SW480 apoptosis induced by chemotherapeutic drugs and calculate the corresponding apoptotic index. Part II: Building 67LR siRNA vector and transfected into SW480 cells, screening and establish 67LR downregulated SW480 transfected cells subline. Part III: cell adhesion assay colon cancer cells stably transfected subline SW480-si67LR control cells with LN and BSA adhesion ability differences; 2. Detected by MTT assay adhere to LN subline SW480-si67LR BSA colon cancer cells stably transfected control cells for chemotherapy drug 5 - fluorouracil (5-Fu) and cisplatin (DDP) drug sensitivity; 3. detected by Annexin V / PI staining adhesion in the the LN and BSA colon cells stably transfected subline SW480-si67LR control cells apoptosis induced by chemotherapeutic drugs, and calculate the apoptotic index; 4 by Western Blot. adhesion to LN and BSA colon cancer cells stably transfected subline the SW480-si67LR its apoptosis signaling pathways associated protein FAK in control cells, total protein and phosphorylated protein, Bcl-2 and Bax. Results: Part I: 1. Per unit time, the LN groups in colon cancer cell line SW480, the number of adherent cells was significantly higher than the BSA group (p lt; 0.05); SW480 colon cancer cell adhesion to BSA phase than chemosensitivity SW480 cell adhesion to LN significant decline the corresponding IC50 for chemotherapy drugs significantly higher, significantly reduced apoptosis induced by chemotherapeutic drugs index; doxorubicin intracellular accumulation and retention were significantly reduced pump drugs out of a significant increase (p lt; 0.05). Part II: successfully screened and establish 67LR downregulated SW480 transfected cells subline. Part III: 1. Per unit time, LN group and colon cancer the 67LR expression levels downward BSA group transfected cells SW480-si67LR number of adherent cells were significantly lower than the control cells (p lt; 0.05); Adhesion and LN, colon transfected cells SW480-si67LR control cells were detected in the expression of the different degree of phosphorylation of FAK, wherein the SW480-si67LR phosphorylation of FAK expression level was significantly lowered, and the relative The expression rate of a statistically significant difference (p LT; 0.05); BSA adhesion with the control component, in colon transfected cells SW480-si67LR control cells were detected in less than phosphorylation of FAK different degrees expression; adhesion component of with LN their control BSA, SW480-si67LR its total FAK expression in control cells without significant difference (p lt; 0.05); 5 with LN adhesion conditions, its control chemosensitivity of colon cancer cells compared 67LR downregulated transfected cells of SW480-si67LR the significant rise in the corresponding significant decrease IC50 for chemotherapy drugs, chemotherapy drug-induced apoptosis index increased significantly; intracellular expression of Bcl-2 significantly reduced, Bax expression was significantly enhanced (p lt; 0.05). Conclusion: LN adhesion and extracellular matrix components, the colon cancer cells may be via the following two ways to enhance their own multi-drug resistance: i improve the ability of tumor cells to drug transporters, leading to chemotherapy drugs in tumor cells accumulated reduction; ii. the ability to enhance the anti-apoptotic, leading to evade apoptosis induced by chemotherapeutic drugs; 2. 67LR is closely related to the adhesion ability of the colon cancer cells down 67LR expression levels of colon carcinoma cell adhesion ability was significantly reduced; 3. LN (extracellular matrix components) When the surface of the membrane of the colon cancer cell line SW480 67LR its specific ligand mutual identification mediated cell adhesion, and may be provided through the induction of intracellular phosphorylation of FAK activation apoptosis related pathway, thereby capable of upregulating the expression levels of Bcl-2 and the downregulation of Bax, thus inhibiting the apoptosis of colon cancer cells in the adhesion state induced by chemotherapeutic drugs.

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CLC: > Medicine, health > Oncology > Gastrointestinal Cancer > Intestinal neoplasms
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