Study On The Functioning Mechanism Of Integrin Activating FAK Mediated Signal Transduction In The Invasion And Metastasis Of Colorectal Carcinoma

Colorectal carcinoma (CRC) is a commonly seen malignancy. Invasion and metastasis are major reasons for clinical therapy failure and patients deaths. Integrin activating focal adhesion kinase (FAK) mediated signal transduction plays an important role in this process. The link between integrins and their ligands promotes the formation of focal adhesion plaque (FAP). Many cytoskeletal proteins, such as talin, paxillin, vinculin and tensin etc, are located in FAP. FAP is the structural basis for integrin sinalling. Besides cytoskeletons, other important signaling molecules, such as FAK, lie in FAP. FAK, a basic molecule for integrin-dependent signal transduction pathway, exerts key roles. The activation and signal transduction of FAK depends on the formation of FAP. FAP associated proteins are classified into two groups: one is structural protein, including vinculin, talin and tensin etc; the other is regulating one, including FAK and paxillin etc.Researches abroad on studying the relation between integrin activating FAK mediated signal transduction and the invasion and metastasis of CRC were conducted with cultured cells, which could not reflect the actual biological properties of tumor cells in vivo, and the protein and mRNA expression of cytoskeletons were not quantified.Domestic researches on integrin activating FAK mediated signal transduction did not involve the relationship with the invasion and metastasisof tumor. No quantitative study on cytoskeletons was reported.So in this research, the expression levels of talin, vinculin, paxillin, tensin and FAK in normal colorectal mucosae, primary CRCs and lymph node metastases were detected using immunohistochemistry, fluorescent quantitative polymerase chain reaction (FQ-PCR) and immunofluorescence combined with confocal laser scanning microscopy. The roles of FAP associated cytoskeletal proteins and FAK during the invasion and metastasis of CRC and their relationships were analyzed. And the mechanism of the signal transduction among integrin, cytoskeletons and FAK in the invasion and metastasis of CRC were explored. Results were as follows:The levels of FAK and paxillin expression increased gradually during the transition from normal colorectal mucosae to malignant lesions and metastasis. The expression levels of FAK and paxillin in CRCs with lymph node metastasis were significantly higher than those without lymph node metastasis. The FAK and paxillin expression, showing no correlation with the differentiation of CRC, were positively correlated with the infiltrating depth of carcinomas.Different from the above results of FAK and paxillin, the expression levels of talin, vinculin and tensin in CRCs were significantly lower than those in normal colorectal mucosae. Compared with the primary CRCs, the lymph node metastases showed even lower expression levels of talin, vinculin and tensin. CRCs with lymph node metastasis had less expression of talin, vinculin and tensin than those without lymph node metastasis. The deeper the carcinomas infiltrated, the lower levels the talin, vinculin and tensin expressed. Similar to FAK and paxillin, the talin, vinculin and tensin expression appeared no significantly correlation with the differentiation of CRCs.The main creative points of this research are as follows:Firstly, this research proved systematically at the mRNA and protein levels that integrin activating FAK mediated signal transduction pathway and its elements played key roles during the development and progression ofCRC. Secondly, this research found that the structural proteins of FAP, including talin, vinculin and tensin, were down-regulated during the development and progression of CRC; whereas the regulating proteins of FAP, including FAK and paxillin, were up regulated, which suggested that FAP exerted binary regulating roles during the development and progression of CRC. Thirdly, this study proposed the mutually modulated relationships between FAK and cytoskeletal proteins and their likely signal transduction pathway.This study shed light on...