Analysis of the function of TM4SF complex and its application of lung cancer therapy.

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Previously, we found that MRP-1/CD9, a member of the tetraspanin family, suppressed cell motility and metastatic potential to lungs. Moreover, reduction of MRP-1/CD9 gene expression was found to be a factor of a poor prognosis for the patients with non-small cell lung cancer, as was another member of TM4SF, KAI1/CD82. On the other hand, CD151 is identical to an exciting gene PETA-3 which may promote tumor metastasis of malignant cells and its expression may be involved in the malignant progression cancer. We have established various stages of lung cancer cell lines and investigated the complex between tetraspsnin family members and integrin family members. Especially, the complex formation of MRP-1/CD9, KAI1/CD82 and PETA3/CD151 were analyzed. In the Stage I, MRP-1/CD9 and KAI1/CD82 expression were found in two cell lines except one, but PETA3/CD151 appeared weak expression. In the Stage II, KAI1/CD82 was decreasing in 5 cases and MRP-1/CD9 was decreasing in 1 case, however PETA3/CD151 was increasing in 2 cases. In the StageIII, only KAI1/CD82was found decreasing in 4 cases. Then only PETA3/CD151 was appeared in the last 1case. In the StageIV, expression of PETA3/CD151 was positive in almost all metastatic cell lines. From these experiments, MRP-1/CD9 and KAI1/CD82 play an important role as metastasis suppressor genes. On the other hand, PETA3/CD151 plays a metastasis promotion gene. Hence, the balance and unbalance of these expressions have something to do with the process of 'metastasis. Besides, we have found that MRP-1/CD9 and KAI1/CD82 regulate VEGF-A gene and Wnt-1 gene. In addition, we have established the monoclonal antibody recognizing MRP-1/CD9-integrin α3 complex. Using this antibody, we will be able to analyze the mechanism of this complex.