Taro Ohba

Combined evaluation of Rad51 and ERCC1 expressions for sensitivity to platinum agents in non-small cell lung cancer

DNA repair enzyme expression in tumor cells possibly affects sensitivity to anti‐cancer agents. The aim of this study was to determine the relationship between expression status of DNA repair enzymes and chemosensitivity in patients with non‐small cell lung cancer (NSCLC). NSCLC tissues prepared from the surgical specimens of 41 patients were subjected to immunohistochemical analysis for Rad51 and ERCC1 proteins and to a chemosensitivity test using the MTT assay. The relationships between the expression status of the DNA repair enzymes and ex vivo chemosensitivity to various agents were evaluated. A positive expression for Rad51 and ERCC1 was observed in 17 cases (41%) and 20 cases (49%), respectively. The positivity of Rad51 was closely related to a certain histologic type of squamous cell carcinoma and poor differentiation, and the positivity of ERCC1 tended to be related to squamous cell carcinoma. In chemosensitivity tests, sensitivities to CDDP and CBDCA were significantly lower when both 2 enzymes were positive (p = 0.012 and 0.04 in CDDP, 0.014 and 0.03 in CBDCA). Both Rad51 and ERCC1 expressions showed no significant relationship with sensitivities to paclitaxel, etoposide, vinorelbine, gemcitabine, 5‐FU, or irinotecan. In conclusion, combined expression of Rad51 and ERCC1 expression is associated with resistance to platinum agents in the ex vivo study of clinical NSCLC, and evaluation of expression status of both DNA repair enzymes would be a predictor for clinical response to platinum‐based chemotherapies.

Never-smoking Nonsmall Cell Lung Cancer as a Separate Entity : Clinicopathologic Features and Survival

To propose ‘never‐smoking nonsmall cell lung cancer (NSCLC)’ as a separate entity, the clinicopathologic differences of operable NSCLC between never‐smoking patients and patients with a history of smoking were investigated.

Effects of excision repair cross-complementation group 1 (ERCC1) single nucleotide polymorphisms on the prognosis of non-small cell lung cancer patients

BACKGROUND Excision repair cross-complementation group 1 (ERCC1) is the lead enzyme in the nucleotide excision repair process. Two polymorphisms of ERCC1, T19007C (rs11615) and C8092A (rs3212986), have been reported to affect both the carcinogenesis and the survival of the patients who received platinum-based chemotherapy, but the mechanism by which these polymorphisms influence the survival is unclear. In this study, we determined the function of these ERCC1 polymorphisms in the survival of NSCLC patients. METHOD The ERCC1 T19007C and C8092A single nucleotide polymorphisms (SNPs) were evaluated in 122 Japanese non-small cell lung cancer (NSCLC) patients who underwent a complete resection and analyzed the clinicopathological significance of these SNPs. None of the patients received peri-operative platinum-based chemotherapy. The relationship between these SNPs and ERCC1 protein expression and the platinum sensitivity of the primary tumors were also examined. RESULT Regarding T19007C SNP, the distribution of the CC, CT, and TT genotypes was 45%, 48% and 7%, respectively. As for C8092A SNP, the distribution of CC and CA genotypes was 70% and 30%, respectively. The patients with C8092A CA genotype were significantly poorer disease-free survival (DFS) and overall survival (OS) than those with the CC genotype (p=0.037 and 0.004). In addition, no relationship was observed between T19007C SNP and DFS or OS. These two SNPs also did not correlate with either ERCC1 protein expression or platinum sensitivity. CONCLUSION The ERCC1 C8092A polymorphism may influence the NSCLC prognosis regardless of the ERCC1 protein expression and platinum sensitivity.

Induction of epithelial-mesenchymal transition-related genes by benzo[a]pyrene in lung cancer cells

It is believed that epithelial‐mesenchymal transition (EMT) occurs during the development and progression of cancer; however, the correlation between tobacco smoking and EMT remains to be elucidated.

Upregulation of Hypoxia-Inducible Factor-1α mRNA and its Clinical Significance in Non-small Cell Lung Cancer

Background: Hypoxia-inducible factor 1α (HIF-1α) is a transcription factor that plays an important role in tumor growth by regulating the energy metabolism and angiogenesis. We herein investigated the mRNA expression level of HIF-1α in non-small cell lung cancer (NSCLC) tissues to clarify the impact on the clinical aspects of NSCLC patients. Experimental Design: HIF-1α mRNA derived from either a tumor or an adjacent lung tissue was quantified using quantitative reverse transcription polymerase chain reaction in 66 patients with NSCLC. The relationship between the mRNA expression level of HIF-1α and clinicopathological factors was investigated. Results: The expression level of HIF-1α mRNA, which correlated with its protein level, was significantly higher in tumor tissue than in the corresponding nontumor-bearing lung tissue (4.22 × 104 ± 4.99 × 104 versus 1.24 × 104 ± 1.15 × 104; p < 0.001). The level of HIF-1α mRNA showed a significantly positive correlation with the mRNA levels of vascular endothelial growth factor and type II hexokinase in tumors (p < 0.0001 for each). In node-negative patients, high expression levels of HIF-1α mRNA in tumors were associated with a poor prognosis (p = 0.0401), but not in the node-positive cases. Conclusion: The expression of HIF-1α mRNA is associated with disease progression in NSCLC tissues, and is expected as a biomarker or therapeutic target.

Benzo[a]pyrene promotes proliferation of human lung cancer cells by accelerating the epidermal growth factor receptor signaling pathway

Smoking is an independent prognostic factor of lung adenocarcinoma. Benzo[a]pyrene (B[a]P) is one of the strongest carcinogens and it is present in both the environment and cigarette smoke. In this study, the effect of B[a]P on the proliferative activity of lung adenocarcinoma cells was investigated. A lung adenocarcinoma cell line, A549, was cultured with B[a]P for various periods, and its proliferative activity was examined by an MTS assay. To investigate the intracellular events related to the proliferative activity, the gene expression profile was investigated by a microarray analysis and a quantitative RT-PCR, and the protein expression and activation status of Akt, ERK 1/2 and the epidermal growth factor receptor (EGFR) were examined by a western blot analysis. Following the culture with B[a]P for 24 weeks, the serum-independent proliferative activity was increased. A microarray analysis revealed that a reversible upregulation of the EGFR and epiregulin genes was recognized in the B[a]P treated cells, in which the overexpression of the phosphorylated EGFR protein was also recognized. The EGFR tyrosine kinase inhibitor reduced the cellular proliferation and the level of phosphorylation of ERK1/2, which is a downstream signal of the EGFR, in the B[a]P-treated A549 cells. Moreover, the B[a]P treatment increased the mRNA expressions of the ligands for EGFR such as amphiregulin and epiregulin. B[a]P increases the proliferative potential of lung adenocarcinoma cells through the EGFR signaling pathway.

Serum carcinoembryonic antigen level is associated with epidermal growth factor receptor mutations in recurrent lung adenocarcinomas

The presence of epidermal growth factor receptor (EGFR) gene mutations is a good indicator of the clinical efficacy of gefitinib in patients with nonsmall cell lung cancer. It was recently reported that the serum carcinoembryonic antigen (CEA) level could be a predictive factor for the efficacy of gefitinib treatment; therefore, it is suggested that the EGFR gene mutation is associated with the serum CEA level. The current study analyzed the association between EGFR gene mutations and clinical features, including the serum CEA level, in patients with recurrent lung adenocarcinomas.

Expression of mismatch repair proteins, hMLH1/hMSH2, in non-small cell lung cancer tissues and its clinical significance

hMLH1 and hMSH2 have been implicated to be involved in the DNA mismatch repair (MMR) system. The purpose of this study is to investigate the expression of hMLH1 and hMSH2 DNA MMR proteins in non‐small cell lung cancer (NSCLC) tissue and to elucidate their clinical significance.

Expression of an X-family DNA polymerase, pol lambda, in the respiratory epithelium of non-small cell lung cancer patients with habitual smoking.

DNA polymerase lambda, pol lambda, is a eukaryotic member of the X-family DNA polymerases that is involved in two modes of DNA repair, i.e. base excision repair (BER) or non-homologous end joining (NHEJ). Using immunohistochemical approaches, we have observed pol lambda expression in human tissues, particularly in the respiratory system of lung cancer patients. pol lambda proteins were distributed in the nuclei of the epithelial cells in the bronchi, bronchioles and alveoli. Intriguingly, the level of pol lambda expression in the bronchiolar epithelia significantly correlated with the amount of habitual smoking in the individuals. Conversely, pol lambda expression in cancer tissues did not correlate with the smoking status of the patients. Pol lambda expression was sometimes discrepant between the tumor tissues and adjacent bronchioles. More importantly, tumors without pol lambda expression that occurred in heavy smokers significantly tended to be at an advanced clinical stage. Pol lambda may thus be involved in the DNA repair processes counteracting DNA damage caused by tobacco smoke in the respiratory system.

Preoperative concurrent chemoradiotherapy of S-1/cisplatin for stage III non-small cell lung cancer.

BACKGROUND Concurrent chemoradiotherapy using S-1 containing tegafur, an oral 5-FU prodrug, plus cisplatin has been reported to show promising efficacy against locally advanced non-small cell lung cancer with acceptable toxicity. The purpose of this study is to assess the impact of this induction treatment followed by surgery on survival for those patients. METHODS Potentially resectable locally advanced non-small cell lung cancer patients were eligible. The concurrent phase consisted of S-1 (orally at 40 mg/m² twice a day on days 1 to 14 and 22 to 36) and cisplatin (60 mg/m² on days 1 and 22) with radiation of 40 Gy/20 fractions beginning on day 1 followed by surgical resection. RESULTS Forty-two consecutive patients, between June 2005 and February 2011, were retrospectively analyzed. The median age was 59 (42 to 77) years, there were 34 males and 8 females, 26 cStage IIIA and 16 IIIB, each 21 adenocarcinomas and others. There were 26 partial responses and 16 stable disease cases after current induction treatment without uncontrollable toxicity. Of the 42 patients, 39 underwent surgical resection; 27 underwent a lobectomy and 12 pneumonectomies. One patient died due to thoracic empyema 65 days after surgery. The median follow-up time was 32.0 months. Three- and 5-year disease-free survival rates in all 39 resected patients were 52.0% and 44.0%, respectively, and 3- and 5-year overall survival rates were 77.4% and 61.7%, respectively. CONCLUSIONS Concurrent chemoradiotherapy using S-1 plus cisplatin followed by surgery may provide a better prognosis for locally advanced non-small cell lung cancer patients. Further prospective clinical investigation should be required.