| Summary: | 博士 === 高雄醫學大學 === 醫學研究所 === 99 === Lung cancer is the leading cause of cancer death worldwide. More than 80% of lung cancer belongs to non-small cell lung cancer (NSCLC). The long-term survival of NSCLC remains suboptimal, with the 5-year survival rate of 15% in all stages. Even in the operable patients the recurrence rate is high, especially the distant recurrence. The determination of lung cancer treatment regimen mainly depends on histopathology and clinical criteria that have only limited power to predict relapse and survival. A major effort to improve the control of the lung cancer entails the use of molecular profiling to characterize tumors and to provide accurate predictions of the outcome after standard or novel treatments. So far, there are only few biomarkers been used as the prediction factors for NSCLC, such as the ERCC1 (excision repair cross-complementing group 1), RRM1 (ribonucleotide reductase messenger 1), beta-III tubulin, EGFR (epidermal growth factor receptor), and BRCA1 (breast cancer gene 1).
Basic helix-loop-helix (bHLH) transcription factors are a group of proteins that function as transcription factors which tightly regulate the expression of cell cycle regulators and orchestrate cell differentiation as well as cell linkage commitment. Id (inhibitor of differentiation/DNA binding) family proteins, including Id1, Id2, Id3 and Id4, belong to the family of helix-loop-helix (HLH) proteins and function as dominant negative regulators of basic HLH transcriptional factors. Overexpression of Id family proteins inhibits cell differentiation and enhances cell proliferation and invasiveness. Although Id1 is the Id family member mostly linked to tumorigenesis, its role in lung cancer is unclear. In this study, an elevated Id1 expression was observed in lung cancer cell lines as well as lung cancer tissues. Id1 overexpression increased cell proliferation while Id1 knockdown decreased cell proliferation, mostly through Akt-related pathway. Nude mice study further confirmed an increased tumor growth in Id1-overexpressed cells and a decreased tumor growth in Id1-knockdown cells. Therefore, inactivation of Id1 may provide a novel strategy for treatment of lung cancer patients.
We also analyze the effect of the various anti-cancer drugs to the expression of the Id protein in the lung cancer cell lines and stable clones. The anticancer drugs (paclitaxel/cisplatin) have shown powerful cytotoxic effect in the Id1 over-expressed cells. In vivo, these cells lines were inoculated subcutaneously into the nude mice which were then treated with paclitaxel/cisplatin to test the drug effect.The tumor growth was inhibited most obviously in the nude mice which had the inoculated tumor of the Id1 over-expressed cells.
Clinically, we retrospectively analyzed our 88 resected lung cancer patients who all had adjuvant chemotherapy with paclitaxel/cisplatin. The patients with high expression of Id1 protein in tumor cytoplasm (expression rate ≧50%) had significant better progression free survival and overall survival time than those of low expression (<50%) (Log Rank test p= 0.022 and 0.005, respectively) (mean progression free survival time, 26.6±2.1 vs.13.9±2.5 months; mean overall survival time, 33.8±1.6 vs.18.8±2.3 months). The result is consistent with the above data both in vitro and in vivo.
In conclusion, we found that the Id1 protein could be used as a favorable prediction factor in resected non-small cell lung cancer patients who were treated with paclitaxel/cisplatin adjuvant chemotherapy.
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