The Prognostic Role of STEAP1 Expression Determined via Immunohistochemistry Staining in Predicting Prognosis of Primary Colorectal Cancer: A Survival Analysis.

STEAP1 (six transmembrane epithelial antigen of the prostate 1) is a transmembrane protein that functions as a potential channel or transporter protein. It is overexpressed in certain cancers and is viewed as a promising therapeutic target. However, the prognostic role of STEAP1 is still controversial, and no role for STEAP1 has yet been indicated in colorectal cancer. The aim of this study was to investigate the possible association of STEAP1 expression with colorectal cancer prognosis. STEAP1 expression was analyzed by immunohistochemical staining of a tissue array of 165 cancer specimens from primary colorectal cancer patients. The mean and medium follow-up times after surgery were 5.1 and 3.9 years, respectively. A total of 139 patients died during the 13 years of follow-up in the survey period. The prognostic value of STEAP1 with respect to overall survival was analyzed by Kaplan-Meier analysis and Cox proportional hazard models. In total, 164 samples displayed detectable STEAP1 expression in the cytoplasm and membrane. Low STEAP1 expression was correlated with poor overall survival (five-year survival: 33.7% vs. 57.0%, low expression vs. high expression, p = 0.020). Accordingly, multivariate analysis identified low STEAP1 expression as an independent risk factor (hazard ratio = 1.500, p = 0.018), especially in elderly patients or those with late stage cancers, late T values, and early N values. We suggest that analysis of STEAP1 expression by immunohistochemical staining could serve as an independent prognostic marker for colorectal patients. This finding should be validated by other investigative groups.

Nickel may contribute to EGFR mutation and synergistically promotes tumor invasion in EGFR-mutated lung cancer via nickel-induced microRNA-21 expression.

We recently reported that nickel accumulation in lung tissues may be associated with an increased in p53 mutation risk via reduced DNA repair activity. Here, we hypothesized that nickel accumulation in lung tissues could contribute to EGFR mutations in never-smokers with lung cancer. We enrolled 76 never-smoking patients to evaluate nickel level in adjacent normal lung tissues by ICP-MS. The prevalence of EGFR mutations was significantly higher in the high-nickel subgroup than in the low-nickel subgroup. Intriguingly, the OR for the occurrence of EGFR mutations in female, adenocarcinoma, and female adenocarcinoma patients was higher than that of all patients. Mechanistically, SPRY2 and RECK expressions were decreased by nickel-induced miR-21 via activation of the EGFR/NF-κB signaling pathway, which promoted invasiveness in lung cancer cells, and particularly in the cells with EGFR L858R expression vector transfection. The patients' nickel levels were associated with miR-21 expression levels. Kaplan-Meier analysis revealed poorer overall survival (OS) and shorter relapse free survival (RFS) in the high-nickel subgroup than in low-nickel subgroup. The high-nickel/high-miR-21 subgroup had shorter OS and RFS periods when compared to the low-nickel/low-miR-21 subgroup. Our findings support previous epidemiological studies indicating that nickel exposure may not only contribute to cancer incidence but also promote tumor invasion in lung cancer.

Nickel accumulation in lung tissues is associated with increased risk of p53 mutation in lung cancer patients.

Occupational exposure to nickel compounds has been associated with lung cancer. The correlation between high nickel levels and increased risk of lung cancer has been previously reported in a case-control study. This study assessed whether nickel exposure increased the occurrence of p53 mutations due to DNA repair inhibition by nickel. A total of 189 lung cancer patients were enrolled to determine nickel levels in tumor-adjacent normal lung tissues and p53 mutation status in lung tumors through atomic absorption spectrometry and direct sequencing, respectively. Nickel levels in p53 mutant patients were significantly higher than those in p53 wild-type patients. When patients were divided into high- and low-nickel subgroups by median nickel level, the high-nickel subgroup of patients had an odds ratio (OR) of 3.25 for p53 mutation risk relative to the low-nickel subgroup patients. The OR for p53 mutation risk of lifetime non-smokers, particularly females, in the high-nickel subgroup was greater than that in the low-nickel subgroup. To determine whether nickel affected DNA repair capacity, we conducted the host cell reactivation assay in A549 and H1975 lung cancer cells and showed that the DNA repair activity was reduced by nickel chloride in a dose-dependent manner. This was associated with elevated production of hydrogen peroxide-induced 8-oxo-deoxyguanosine. Therefore, increased risk of p53 mutation due to defective DNA repair caused by high nickel levels in lung tissues may be one mechanism by which nickel exposure contributes to lung cancer development, especially in lifetime female non-smokers.

Pulmonary CYP2A13 levels are associated with early occurrence of lung cancer-Its implication in mutagenesis of non-small cell lung carcinoma.

CYP2A13, a human pulmonary specific cytochrome P450 enzyme, plays an important role in susceptibility to tobacco-specific nitrosamines (TSNAs)-induced lung cancer in humans. The pattern of CYP2A13 distribution in respiratory tract affects the susceptibility of the lung to carcinogens. CYP2A13 is expressed in the epithelium of trachea and bronchi; however its pattern of expression in human lung cancer remains largely unknown. This study aimed to determine the CYP2A13 expression in specimens from human non-small cell lung carcinomas (NSCLCs), i.e., adenocarcinoma and squamous carcinoma, by immunohistochemical (IHC) analysis and to identify the potential linkage between tumor CYP2A13 levels and some clinicopathological characteristics of NSCLC patients in Taiwan. The tumor CYP2A13 IHC staining signal was strong in 76% of the 112 study subjects. Study subjects (especially non-smoking or lung adenocarcinoma patients) with higher tumor CYP2A13 levels were younger. Multiple logistic regression analysis revealed that in younger subjects (age ≤ 66) and heavy smokers (pack-years ≥ 40), the odds ratio (OR) for positive tumor CYP2A13 staining was significantly higher than that for negative tumor CYP2A13 staining. Moreover, the association of EGFR gene mutations and positive tumor CYP2A13 staining was also revealed. In conclusion, these findings suggest the potential involvement of pulmonary CYP2A13 in the early occurrence of NSCLC as well as in the development of EGFR gene mutations.

GSTP1 genetic polymorphism is associated with a higher risk of DNA damage in pesticide-exposed fruit growers.

Pesticide exposure is associated with various neoplastic diseases and congenital malformations. Animal studies also indicated that pesticides may be metabolized by cytochrome P450 3A5 (CYP3A5) enzymes, paraoxonases (PON1 and PON2), or glutathione S-transferases (GSTM1, GSTT1, and GSTP1). However, little is known about the genotoxicity of pesticides in people with various genetic polymorphisms of human CYP3A5, PON1, PON2, GSTM1, GSTT1, and GSTP1. Thus, this study was designed to investigate whether various metabolic genotypes are more susceptible to DNA damage in pesticide-exposed fruit growers. Using the Comet assay, the extent of DNA damage was evaluated in the peripheral blood of 91 fruit growers who experienced pesticide exposure and 106 unexposed controls. Questionnaires were administered to obtain demographic data, cigarette smoking habits, medical, and occupational histories. The genotypes for CYP3A5, PON1, PON2, GSTM1, GSTT1, and GSTP1 genes were identified by PCR. The results showed that subjects experiencing high or low pesticide exposure had a significantly greater DNA tail moment (DAN damage) than did controls. The multiple regression model also revealed that age (P < 0.01), high pesticide exposure (P < 0.01), low pesticide-exposure (P < 0.01), and CYP3A5 (P = 0.04) and GSTP1 (P = 0.02) genotypes were significantly associated with an increased DNA tail moment. Further analysis of environmental and genetic interactions revealed a significant interaction for GSTP1 genotypes to influence DNA tail moment for the high pesticide exposure group. These results suggest that individuals with susceptible metabolic GSTP1 genotypes may experience an increased risk of DNA damage elicited by pesticide exposure.