Search

Introduction: Proline-rich protein 11 (PRR11) functions in the progression of cell cycle, and silencing the PRR11 gene in lung cancer cells results in the inhibition of cellular proliferation, cell cycle progression, cell migration, invasion and colony formation. PRR11 may therefore be a therapeutic target in lung cancer., Materials and Methods: Microarrays of surgical specimens of non-mucinous invasive adenocarcinoma of the lung, from 346 subjects that were not given preoperative therapy, were autoimmunostained with PRR11 and, except for trace and pseudo-positivity, assessed as "positive" at any proportion and intensity., Results: PRR11 immunoreactivity demonstrated a tendency to associate with an aggressive phenotype (tumor size, vascular invasion, and adjuvant therapy) and some effect on overall survival (Hazard ratio 1.51)., Conclusions: PRR11 may be a weak prognostic indicator of overall survival of patients with non-mucinous invasive adenocarcinoma of the lung.

Objectives: Partner of Sld five (Psf) 3 is a member of the evolutionarily conserved heterotetrameric complex GINS (Go-Ichi-Ni-San). We previously reported that Psf3 could serve as a biomarker of poor prognosis in lung adenocarcinoma. Here, we used tissue microarrays to analyse Psf3 expression in lung adenocarcinoma and investigated whether its expression is associated with survival outcomes., Methods: The study included 864 consecutive patients with lung adenocarcinoma who underwent complete resection at Hyogo Cancer Center between January 2002 and December 2009. Tissue microarrays were prepared, and Psf3 was detected using mouse antihuman Psf3 primary monoclonal antibodies. The status of Psf3 expression was determined using these microarrays., Results: Of the 864 patients, 375 had high-positive Psf3 expression and 489 had low-positive expression. Psf3 expression was significantly associated with age, sex, T factor, lymph node metastasis, stage and P factor. The 5-year disease-free survival (DFS) rate was significantly lower in patients with high-positive Psf3 expression than in those with low-positive expression, and Psf3 expression, sex, age, T factor and lymph node metastasis were identified as independent and significant prognostic determinants. Among patients with Stage I adenocarcinoma, the 5-year DFS rate was significantly lower in those with high-positive Psf3 expression than in those with low-positive expression, and Psf3 expression was the most powerful survival predictor., Conclusions: The present findings strengthened our previous data demonstrating that high Psf3 expression in primary lung adenocarcinoma plays an important role in disease progression and is a prognostic indicator, particularly in early-stage adenocarcinoma., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: We evaluated the clinical benefit of segmentectomy for patients with cT1bN0M0 lung cancer., Methods: We retrospectively reviewed the medical records of 178 patients who underwent lobectomy or segmentectomy for cT1bN0M0 lung adenocarcinoma and squamous cell carcinoma from January 1995 to December 2005. We investigated the association of surgical outcomes with the presence of pathological invasion., Results: The median follow-up period was 93.4 months. Of 178 patients, 37 were scheduled for segmentectomy, but 6 of these patients were switched to receive lobectomy due to surgical N1 or N2 in 3 patients and insufficient surgical margins in 3 patients. In total, 31 patients underwent segmentectomy, and 147 underwent lobectomy. The 5-year overall survival (OS) was similar between the patients who underwent lobectomy (5-year OS, 81.6%) and segmentectomy (5-year OS, 77.4%, P = 0.73). Among pN0 patients without pathological invasion, there was no difference in OS between patients who underwent lobectomy (5-year OS, 89.9%) and segmentectomy (5-year OS, 88.9%, P = 0.80). In contrast, among pN0 patients with pathological invasion, OS was greater in patients who underwent lobectomy (5-year OS, 80.9%) than in those who underwent segmentectomy (5-year OS, 54.6%; P = 0.19). Moreover, a significantly higher rate of local and local + distant recurrence was observed in patients who underwent segmentectomy (45%) than in those who underwent lobectomy (15%) in this group (P = 0.02)., Conclusions: The results of our study suggest that segmentectomy may not be recommended for cT1b tumours if pathological invasion is suspected before surgery., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Positive pleural lavage cytology (PLC) findings are considered to be predictive of a poor prognosis in patients with non-small-cell lung cancer (NSCLC). We investigated the clinical benefit of adjuvant chemotherapy for lung adenocarcinoma patients with positive PLC findings., Methods: We retrospectively reviewed the medical records of lung adenocarcinoma patients who underwent tumour resection and had positive PLC findings between January 2000 and December 2009., Results: Fifty-three patients (4.8%) of 1114 patients with lung adenocarcinoma had positive PLC findings. The median follow-up period was 33.6 months. Adjuvant chemotherapy was administered to 24 patients (adjuvant chemotherapy group); 7, 8 and 9 patients had pathological Stage I, II and III, respectively . The surgery-alone group comprised 29 patients; 12, 8 and 9 patients had pathological Stage I, II and III, respectively. The 5-year recurrence-free survival (RFS) rates were 34.6 and 15.7% (P < 0.01) in adjuvant chemotherapy and surgery-alone groups, respectively. The rate of distant recurrence was significantly reduced in the adjuvant chemotherapy group (25.0 and 58.6%; P = 0.01). Even for Stage I cases, adjuvant chemotherapy tended to improve the 5-year RFS rate compared with surgery alone (60.1 and 29%; P = 0.11). Multivariate analysis for RFS revealed that adjuvant chemotherapy [hazard ratio (HR), 0.45; P = 0.03], tumour size >30 mm (HR, 2.23; P = 0.02) and lymph node metastasis (HR, 2.67; P < 0.01) were significant independent prognostic factors for recurrence., Conclusions: Adjuvant chemotherapy for lung adenocarcinoma patients with positive PLC findings significantly improved recurrence-free survival., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Nectin-like molecule-5 (Necl-5) is an immunoglobulin-like molecule that was originally identified as a poliovirus receptor and is often upregulated in cancer cells. It has been said that Necl-5 plays a role in not only cell-cell adhesion, but also cell migration, proliferation, and metastasis. In this study, we used a bronchioloalveolar carcinoma (BAC) cell line and fibroblasts to assess the expression of Necl-5 in the development of cancer-stroma communication by using an easy-to-prepare double-layered collagen gel hemisphere (DL-CGH) system that enables visualization of cell migration during invasion. The expression of Necl-5 was higher in BAC cells than in fibroblasts. This tendency didn't change even when the BAC cells were mixed with fibroblasts. To assess the role of Necl-5 in the invasive activity of the BAC cells, we knocked down its expression using RNA interference (RNAi). The invasion assay with DL-CGH revealed that inhibition of Necl-5 expression in the BAC cells was associated with suppressed invasiveness. In addition, Necl-5 knockdown inhibited the movement and proliferation of the BAC cells. Necl-5 expression in lung cancer cells is crucial for their invasiveness in the cancer-stromal interaction, suggesting that Necl-5 could be a favorable molecular target for the suppression of invasiveness in lung adenocarcinoma., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Psf3 is a member of the evolutionarily conserved heterotetrameric complex GINS (Go-Ichi-Ni-San), which consists of Sld5, Psf1, Psf2, and Psf3. Previous studies have suggested that some GINS complex members are upregulated in cancer, but the status of Psf3 expression in lung adenocarcinoma has not been investigated. The objective of the current study was to determine whether Psf3 plays a role in lung adenocarcinoma by investigating clinical samples. We investigated the status of Psf3 expression in cancer cells of 125 consecutive resected lung adenocarcinomas by immunohistochemistry. Increased Psf3 expression was observed in 27 (21.6%) of the 125 cases. Further, univariate analysis and log-rank test indicated a significant association between Psf3 expression and lower overall survival rate (P = 0.0001 and P < 0.0001, respectively). Multivariate analysis also indicated a statistically significant association between increased Psf3 expression and lower overall survival rate (hazard ratio, 5.2; P = 0.0027). In a subgroup analysis of only stage I patients, increased Psf3 expression was also significantly associated with a lower overall survival rate (P = 0.0008, log-rank test). Moreover, the Ki67 index level was higher in the Psf3-positive group than in the Psf3-low positive group (P < 0.0001, Mann-Whitney U-test). Our results indicated that Psf3 can serve as a prognostic biomarker in lung adenocarcinoma., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

DNA damage response pathways are important for maintaining genomic stability. The oncogenic phosphatase Wip1 plays a crucial role in DNA damage response by inhibiting several cell cycle proteins, including p53. Although Wip1 gene amplification has been reported in various primary tumors, including lung cancer, its biological significance for survival of primary lung tumor patients remains unclear. We investigated the expression of Wip1 in cancer epithelial cells immunohistochemically in 84 consecutive resected cases of lung adenocarcinoma. Increased Wip1 expression was observed in 54 (64.3%) of the 84 cases. Wip1 expression was found to be correlated significantly with two clinicopathological factors: γ-H2AX expression, and invasion to the pulmonary vein. A univariate analysis and log-rank test indicated a significant association between Wip1 expression and lower overall survival rate (P = 0.019 and P = 0.0099, respectively). A multivariate analysis also indicated a statistically significant association between increased Wip1 expression and lower overall survival rate (hazard ratio, 4.3; P = 0.026). The Ki67 index level was higher in the Wip1-positive group than in the negative group (P < 0.04, Mann-Whitney U-test). Moreover, in a subgroup analysis of only stage I patients, increased Wip1 expression was also significantly associated with a lower overall survival rate (P = 0.023, log-rank test). These results indicate that the increased expression of Wip1 in cancer epithelial cells has significant value for tumor progression and the clinical prognosis of patients with primary lung adenocarcinoma., (© 2011 Japanese Cancer Association.)

Nectin-like molecule-5 (Necl-5) is an immunoglobulin (Ig)-like molecule that is up-regulated in many types of cancer cells. It was shown experimentally that Necl-5 enhances cell migration, proliferation, and metastasis, but its clinical significance has not been documented. The aim of this study was to observe the expression of Necl-5 in surgically resected primary lung adenocarcinomas and to investigate its clinical significance. A total of 63 surgically resected primary pulmonary adenocarcinoma tissues were investigated by immunohistochemistry for the expression of Necl-5. The relationship between expression of Necl-5 and clinicopathological features was analyzed, and the influence of Necl-5 expression on outcomes in these patients was assessed. A strong expression of Necl-5 by cancer cells was observed in 43 of the 63 tumors. The overexpression of Necl-5 by cancer cells was significantly associated with lymph node metastasis (P = 0.0398), TNM staging (P = 0.0367), and the bronchioloalveolar carcinoma ratio of tumors (P = 0.0423). Furthermore, the disease-free survival rate in patients with positive Necl-5 overexpression was significantly lower than that in patients with negative Necl-5 overexpression (P = 0.0004). Multivariate survival analysis revealed Necl-5 expression to be an independent risk factor for an unfavorable outcome (P = 0.0294). Additionally, an analysis including only the stage I cases revealed that the disease-free survival rate of the Necl-5-positive group was significantly lower than that of the Necl-5-negative group (P = 0.0192). These results indicate that Necl-5 plays a role in mediating tumor cell invasion and that the overexpression of Necl-5 in cancer cells has clinical significance for prognostic evaluation of patients with primary pulmonary adenocarcinoma.

Background: Several reports have revealed the association between single nucleotide polymorphisms (SNPs) and the development of cancer. Although many SNPs have been investigated, they were tested individually. In this study, nonsynonymous SNPs present in DNA damage response genes were comprehensively analyzed for lung cancer susceptibility., Methods: The authors selected 37 nonsynonymous SNPs in 23 genes involved in DNA damage repair pathways. Fifty lung adenocarcinoma patients resected at their institution between 2002 and 2005 and 50 individuals without any known history of cancer were recruited for a case-control study., Results: Three variants (XRCC1 194Trp homozygotes, POLdelta1 119His homozygotes, and RAD9 239Arg heterozygotes) tended to coassociate with lung cancer risk. The authors analyzed and calculated whether the association between combinations of these 3 SNPs significantly affected the risk of lung cancer. Compared with carriers of either XRCC1 194Trp homozygote or RAD9 239Arg heterozygote variants, noncarriers were at a significantly decreased risk for lung cancer (odds ratio [OR], 0.282; confidence interval [CI], 0.089-0.893). The same results were found for the combination of POLdelta1 119His homozygotes and RAD9 239Arg heterozygotes (OR, 0.277; CI, 0.077-0.993). Moreover, compared with carriers that had at least 1 of the 3 variants, noncarriers showed a more significant decrease in risk (OR, 0.263; CI, 0.090-0.767)., Conclusions: Analysis of the presence of XRCC1 194Trp homozygote, POLdelta1 119His homozygote, and RAD9 239Arg heterozygote variants revealed that their coassociation leads to a significant risk for the development of lung adenocarcinoma. Inclusive analyses of different SNPs were important in this cancer risk study.

FOXO1 (FKHR), one of the forkhead family of transcription factors, is involved in proapoptotic signaling. Phosphorylated Akt leads to the inhibition of FOXO1 activity by direct phosphorylation and cytoplasmic sequestration. We investigated the localization of FOXO1 in non-small cell lung cancer (NSCLC) cell lines grown in a variety of media. FOXO1 expression in tissue microarrays of clinical NSCLC samples was analyzed immunohistochemically. Significant correlations between these data were assessed in order to discern the relationship between Akt and apoptosis. While FOXO1 localized to the nucleus in cell lines cultured without FBS, FOXO1 translocated from the nucleus to the cytoplasm in cell lines cultured with fetal bovine serum (FBS). Inhibition of Akt using RNA interference resulted in the accumulation of FOXO1 in A549 and EBC1 cell nuclei, and in accelerated apoptosis induction. In NSCLC cells, where FOXO1 was present in the cytoplasm constitutively, inhibition of Akt led to FOXO1 translocation to the nucleus and initiation of apoptosis. Using immunohistochemistry and immunofluorescence to examine the expression of FOXO1 in 185 surgically resected, paraffin-embedded stage I-IV tumor samples, we observed a significant correspondence between positive staining for FOXO1 in early stage tumors and in tumors without nodal involvement; in contrast, no significant relationship was observed between FOXO1 expression and tumor status, lymphatic invasion, or venous invasion. Moreover, induction of apoptosis was vigorous in NSCLC cells expressing FOXO1. These results suggest that FOXO1 expression is a favorable prognostic factor in NSCLC.

Background: It was previously reported that a functional human (h) Rad9 protein accumulated in the nuclei of non-small cell lung carcinoma (NSCLC) cells. Those experiments, however, did not examine whether the hRad9 gene was mutated in those cells. The sequence of the HRAD9 gene in NSCLC cells was investigated., Methods: The sequence of the HRAD9 was examined in tumor and peripheral normal lung tissues obtained from 50 lung adenocarcinoma patients during surgery. The expression of its mRNA using reverse transcription polymerase chain reaction (RT-PCR) was also examined., Results: No sequence alterations were detected in the HRAD9 gene, which was found to be normally transcribed in surgically resected lung carcinoma cells. However, in eight (16.0%) cases a single nucleotide polymorphism (SNP) was observed at the second position of codon 239 (His/Arg heterozygous variant) of the gene. This frequency was significantly higher than that found in the normal population., Conclusions: Whereas the capacity to produce a functional hRad9 protein was intact in lung adenocarcinoma cells, a nonsynonymous SNP of HRAD9 was detected that might be associated with the development of lung adenocarcinoma.