Long Noncoding RNA PTPRG Antisense RNA 1 Reduces Radiosensitivity of Nonsmall Cell Lung Cancer Cells Via Regulating MiR-200c-3p/TCF4.

BACKGROUND: PTPRG antisense RNA 1 has been well-documented to exert an oncogenic role in diverse neoplasms. However, the precise role of PTPRG antisense RNA 1 in regulating radiosensitivity of nonsmall cell lung cancer cells remains largely elusive. METHODS: Expression levels of PTPRG antisense RNA 1 and miR-200c-3p in nonsmall cell lung cancer tissues and cells were detected by quantitative real-time polymerase chain reaction, while transcription factor 4 expression was examined by immunohistochemistry and Western blot. After nonsmall cell lung cancer cells were exposed to X-ray with different doses in vitro, Cell Counting Kit-8 assay and colony formation assay were conducted to determine the influence of PTPRG antisense RNA 1 on cell viability. Interaction between miR-200c-3p and PTPRG antisense RNA 1 as well as transcription factor 4 was investigated by dual luciferase reporter assay. RESULT: In nonsmall cell lung cancer tissues, the expressions of PTPRG antisense RNA 1 and transcription factor 4 were significantly upregulated, whereas the expression of miR-200c-3p was downregulated. It was also proved that PTPRG antisense RNA 1 and 3'-untranslated region of transcription factor 4 can bind to miR-200c-3p. Under X-ray irradiation, overexpressed PTPRG antisense RNA 1 could promote the viability and enhance the radioresistance of nonsmall cell lung cancer cells, and this effect was partially weakened by miR-200c-3p mimics. Transcription factor 4 was identified as a target gene of miR-200c-3p, which could be positively regulated by PTPRG antisense RNA 1. CONCLUSION: PTPRG antisense RNA 1 reduces the radiosensitivity of nonsmall cell lung cancer cells via modulating miR-200c-3p/TCF4 axis.

Exosome-Reversed Chemoresistance to Cisplatin in Non-Small Lung Cancer Through Transferring miR-613.

INTRODUCTION: Non-small lung cancer (NSCLC) is one of the most common malignant tumors in the world. Chemoresistance is the main reason of adverse effects leading to the death of patients; thus, it is important to discover the potential target of chemotherapeutic resistance. METHODS: The expression of differentially expressed miRNA was detected in BEAS-2B, A549 and A549/cisplatin (DDP) by qRT-PCR. Transmission electron microscopy (TEM) and exosome biomarkers were used to validate the extracted exosome. Cells incubated with miR-613 enriched exosomes were used to detect the function of exo-miR-613 in vitro. Then, exo-miR-613 was injected to mice treated with DDP to investigate the function role of exo-miR-613 in vivo. RESULTS: Comparing to BEAS-2B, the expression of miR-613 inA549 was significantly reduced, which was more obvious in A549/DDP. After incubated with exo-miR-613 and corresponding exo-negative control (NC), we found overexpression of miR-613 remarkably increased the inhibition of cell proliferation induced by cisplatin. Exo-miR-613 fused into cells to significantly enhance the inhibited effect of DDP on the proliferation, migration and showed a promotion on cell apoptosis and DNA damage. The in vivo study showed that exo-miR-613 significantly inhibited the tumor growth, and promote the sensitivity to DDP, probably by down-regulating the expressions of GJA1, TBP and EIF-4E in tumor cells and tissues. CONCLUSION: Exo-miR-613 reversed chemoresistance to DDP in NSCLC cell to involve in the process of tumor progression, and might be a potential therapeutic strategy for NSCLC.

High Expression of Krüppel-like Factor 7 Indicates Unfavorable Clinical Outcomes in Patients with Lung Adenocarcinoma.

BACKGROUND: Krüppel-like factor 7 (KLF7), which belongs to the KLF family of zinc finger transcription factors, plays a critical role in regulating gene expression. It was reported that KLF7 overexpression was closely related to the progression of gastric cancer. However, the role of KLF7 in lung adenocarcinoma (LAC) has not been elucidated. The aim of our study is to investigate the expression pattern of KLF7 and explore whether the KLF7 expression is correlated with unfavorable clinical outcome of patients with LAC. MATERIALS AND METHODS: The protein and mRNA levels of KLF7 were examined in LAC tissues by using immunohistochemistry staining and quantitative reverse transcription polymerase chain reaction, respectively. The prognostic role of KLF7 in patients with LAC was assessed using univariate and multivariate analyses. Clinical outcomes were evaluated by Kaplan-Meier analysis and logrank test. The effects of KLF7 on lung cancer cells were investigated through cellular experiments. RESULTS: KLF7 expression was elevated in LAC tissues compared with adjacent normal tissues. High protein level of KLF7 was correlated with larger tumor size, positive lymph node metastasis, and advanced TNM stage. Moreover, patients with LAC with higher expression level of KLF7 had poorer overall survival, and KLF7 was identified as an unfavorable independent prognosis factor. Knockdown of KLF7 can suppress the proliferation and invasion abilities of cancer cells. CONCLUSIONS: Our studies revealed that high KLF7 expression level was significantly associated with the poorer clinical outcomes of patients with LAC, indicating the potential role of KLF7 as a novel prognostic biomarker and therapeutic target.

Ataxia Telangiectasia-Mutated (ATM)Polymorphisms and Risk of Lung Cancer in a Chinese Population.

BACKGROUND: The ataxia telangiectasia-mutated (ATM) gene has a key role in DNA repair including activation and stabilization of p53, which implicates the importance of ATM polymorphisms in the development of cancer. This study aims to investigate the association of two ATM single-nucleotide polymorphisms (SNPs) with lung cancer, as well as their potential interaction with p53 gene and other known risk factors of lung cancer. METHODS: A population-based case-control study was conducted in Taiyuan city, China with 399 cases and 466 controls matched on the distribution of age and sex of cases. The two ATM gene SNPs, ATMrs227060 and ATMrs228589 as well as p53 gene SNP, p53rs1042522 were genotyped using Sequenom platform. Unconditional logistic regression models were used to estimate crude and adjusted odds ratios (aOR) and 95% confidence intervals (CIs). Adjusted models controlled for age, sex, and smoking status. RESULTS: The study showed that TT genotype of ATMrs227060 (aOR = 1.58, 95% CI: 1.06-2.35) and AA genotype of ATMrs228589 were significantly associated with lung cancer (aOR = 1.50, 95% CI: 1.08-2.08) in a recessive model. Additionally, carrying variant genotypes of ATMrs227060 (TT), ATMrs228589 (AA), and p53rs1042522 (CC) concomitantly was associated with much higher risk (aOR = 3.68, 95% CI: 1.43-9.45) of lung cancer than carrying variant genotypes of any one of the above three SNPs. We also found multiplicative and additive interaction between tea drinking and ATMrs227060 in association with lung cancer. CONCLUSION: This study indicates that ATM gene variants might be associated with development of lung cancer in Chinese population. These results need to be validated in larger and different population samples.

Life-Style Habits in a High-Risk Area for Upper Gastrointestinal Cancers: a Population-Based Study from Shanxi, China.

BACKGROUND: Cancer is a burden on humanity and ranks as a leading cause of morbidity and mortality in China. Shanxi province has its unique cancer patterns and the burden is increasing. In this study, we aimed to assess the pattern of dietary habits and life-style in Shanxi, a high-risk area for upper gastrointestinal cancers in China and further evaluate the trends in cancer incidence and mortality based on registered data. MATERIALS AND METHODS: Data on lifestyle, diet, physical activity were obtained from the household health survey at Zhongyang from 2013 to 2015. Cancer diagnoses were reported to Shanxi Center for Disease Control and Prevention (SCDCP). Population-based cancer incidence data and mortality data of 2012 were collected from the SCDCP. All incidence and death rates were expressed per 100,000 populations. Univariate analysis was performed using the Chi-squared test or Fisherandapos;s exact test. RESULTS: Overall, deficiencies in fresh fruits and vegetable food, and intake of hot food, salted food, or pickled food are serious problems in Shanxi, especially in rural areas. Upper gastrointestinal cancers were the most commonly diagnosed cancers, and the incidence in rural areas is higher than those in urban areas. Cervical cancer is the most common cancer for females. Moreover, the agespecific incidence exhibited an increased trend before 40 years old. Consistent with the previous literature, our epidemiological investigation results suggest that lifestyle, nutrition deficient, and infections were major risk factors for upper gastrointestinal cancers or cervical cancer in Shanxi. Facing a serious situation, we further explored defensible recommendations for the general public in order to promote changes in environments that support healthful eating and physical activity habits, to reduce cancer risk. CONCLUSIONS: Our results present the current cancer trends in Shanxi and its related etiologic risk factors and provide a theoretical basis to guide public health efforts to prevent and control cancers in the province.

Raw Garlic Consumption and Lung Cancer in a Chinese Population.

BACKGROUND: Evidence of anticancer properties of garlic for different cancer sites has been reported previously in in vitro and in vivo experimental studies but there is limited epidemiologic evidence on the association between garlic and lung cancer. METHODS: We examined the association between raw garlic consumption and lung cancer in a case-control study conducted between 2005 and 2007 in Taiyuan, China. Epidemiologic data was collected by face-to-face interviews from 399 incident lung cancer cases and 466 healthy controls. We used unconditional logistic regression models to estimate crude and adjusted ORs (aOR) and their 95% confidence intervals (CI). Adjusted models controlled for age, sex, average annual household income 10 years ago, smoking, and indoor air pollution. RESULTS: Compared with no intake, raw garlic intake was associated with lower risk of development of lung cancer with a dose-response pattern (aOR for <2 times/week = 0.56; 95% CI, 0.39-0.81 and aOR for ≥2 times/week = 0.50; 95% CI, 0.34-0.74; Ptrend = 0.0002). Exploratory analysis showed an additive interaction of raw garlic consumption with indoor air pollution and with any supplement use in association with lung cancer. CONCLUSIONS: The results of the current study suggest that raw garlic consumption is associated with reduced risk of lung cancer in a Chinese population. IMPACT: This study contributes to the limited research in human population on the association between garlic and lung cancer and advocates further investigation into the use of garlic in chemoprevention of lung cancer. Cancer Epidemiol Biomarkers Prev; 25(4); 624-33. ©2016 AACR.

TP53 genetic polymorphisms, interactions with lifestyle factors and lung cancer risk: a case control study in a Chinese population.

BACKGROUND: A pathway-based genotyping analysis suggested rs2078486 was a novel TP53 SNP, but very few studies replicate this association. TP53 rs1042522 is the most commonly studied SNP, but very few studies examined its potential interaction with environmental factors in relation to lung cancer risk. This study aims to examine associations between two TP53 single-nucleotide polymorphisms (SNPs) (rs2078486, rs1042522), their potential interaction with environmental factors and risk of lung cancer. METHODS: A case-control study was conducted in Taiyuan, China. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Multiplicative and additive interactions between TP53 SNPs and lifestyle factors were evaluated. RESULTS: Variant TP53 rs2078486 SNP was significantly associated with elevated lung cancer risk among smokers (OR: 1.70, 95% CI: 1.08 - 2.67) and individuals with high indoor air pollution exposure (OR: 1.51, 95% CI: 1.00-2.30). Significant or borderline significant multiplicative and additive interactions were found between TP53 rs2078486 polymorphism with smoking and indoor air pollution exposure. The variant genotype of TP53 SNP rs1042522 significantly increased lung cancer risk in the total population (OR: 1.57, 95% CI: 1.11-2.21), but there was no evidence of heterogeneity among individuals with different lifestyle factors. CONCLUSIONS: This study confirmed that TP53 rs2078486 SNP is potentially a novel TP53 SNP that may affect lung cancer risk. Our study also suggested potential synergetic effects of TP53 rs2078486 SNP with smoking and indoor air pollution exposure on lung cancer risk.

Genetic polymorphisms of TERT and CLPTM1L and risk of lung cancer--a case-control study in a Chinese population.

BACKGROUND/OBJECTIVES: Genetic variants of telomerase reverse transcriptase (TERT) and cleft lip and palate trans-membrane 1 like (CLPTM1L) genes in chromosome 5p15.33 region were previously identified to influence the susceptibility to lung cancer. We examined the association of single nucleotide polymorphisms (SNPs) in TERT and CLPTM1L genes with lung cancer and explored their potential modifying effects on the relationship between environmental risk factors and lung cancer in a Chinese population. METHODS: We genotyped rs2736100 (TERT) and rs401681 (CLPTM1L) SNPs in a case-control study with 399 lung cancer cases and 466 controls form Taiyuan, China. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. Potential confounders were controlled for in the adjusted models. RESULTS: We found that the GG genotype of TERT was positively associated with lung cancer (OR=1.47, 95% CI: 1.00-2.16). The association was stronger in participants older than 60years, exposed to low indoor air pollution and adenocarcinoma and squamous cell carcinoma (SCC) in recessive model analysis. The GA genotype of CLPTM1L was inversely associated with lung cancer (OR=0.72, 95% CI: 0.54-0.97). The association was stronger in participants 60 years old or younger, males, heavy smokers, exposed to low indoor air pollution and SCC in dominant model analysis. Individuals carrying both TERT and CLPTM1L risk genotypes had higher risk of lung cancer (OR=1.80, 95% CI: 1.15-2.82). Significant interaction was observed between CLPTM1L and indoor air pollution in association with lung cancer. CONCLUSIONS: Our results reiterate that genetic variants of TERT and CLPTM1L contribute to lung cancer susceptibility in Chinese population. These associations need to be verified in larger and different populations.

Indoor air pollution and risk of lung cancer among Chinese female non-smokers.

PURPOSE: To investigate indoor particulate matter (PM) level and various indoor air pollution exposure, and to examine their relationships with risk of lung cancer in an urban Chinese population, with a focus on non-smoking women. METHODS: We conducted a case-control study in Taiyuan, China, consisting of 399 lung cancer cases and 466 controls, of which 164 cases and 218 controls were female non-smokers. Indoor PM concentrations, including PM(1), PM(2.5), PM(7), PM(10), and TSP, were measured using a particle mass monitor. Unconditional logistic regression models were used to calculate odds ratios (ORs) and 95 % confidence intervals after adjusting for age, education, annual income, and smoking. RESULTS: Among non-smoking women, lung cancer was strongly associated with multiple sources of indoor air pollution 10 years ago, including heavy exposure to environmental tobacco smoke at work (aOR = 3.65), high frequency of cooking (aOR = 3.30), and solid fuel usage for cooking (aOR = 4.08) and heating (aOR(coal stove) = 2.00). Housing characteristics related to poor ventilation, including single-story, less window area, no separate kitchen, no ventilator, and rarely having windows open, are associated with lung cancer. Indoor medium PM(2.5) concentration was 68 µg/m(3), and PM(10) was 230 µg/m(3). PM levels in winter are strongly correlated with solid fuel usage for cooking, heating, and ventilators. PM(1) levels in cases are more than 3 times higher than that in controls. Every 10 µg/m(3) increase in PM(1) is associated with 45 % increased risk of lung cancer. CONCLUSIONS: Indoor air pollution plays an important role in the development of lung cancer among non-smoking Chinese women.

Differentiating malignant colorectal tumor patients from benign colorectal tumor patients by assaying morning urinary arylsulfatase activity.

AIM: For several decades urinary arylsulfatase (ARS) activity has been reported to be elevated in many cancers. It has been shown that urinary ARS activity may serve as a marker of tumor progression and therapy surveillance. This study was designed to evaluate the clinical application of detection of urinary ARS activity. METHODS: We used a modified precipitation method to separate ARS from urine samples. This method was easy to use and applicable for a high throughput assay. We tested and analyzed the morning urinary ARS activity in 300 normal controls, 97 patients with benign tumors and 119 with malignant colorectal tumor. RESULTS: Compared to normal male and female controls, morning urinary ARS activity was significantly higher in malignant colorectal tumor patients. Moreover, morning urinary ARS activity had a relatively high efficacy in distinguishing patients with malignant colorectal tumors from those with benign colorectal tumors. The area under the curve in the receiver operator characteristics curve analysis was 0.89 (95% CI, 0.83-0.95) and 0.87 (95% CI, 0.79-0.94) in male and female colorectal patients, respectively. CONCLUSION: These data suggest the potential application of morning urinary ARS activity to conventional clinical use.

Use of serum circulating CCNB2 in cancer surveillance.

Cyclin B2 (CCNB2), a member of the cyclin protein family, has been found to be up-regulated in human cancers. To evaluate the potential use of circulating CCNB2 in serum in cancer surveillance, we examined relative expression levels of serum circulating CCNB2 mRNA in 103 cancer patients, 19 normal controls, and 40 benign disease patients using real-time quantitative reverse transcriptase polymerase chain reaction. We found that the relative expression level of circulating CCNB2 mRNA in cancer patients was significantly higher (p<0.0001) than that in normal controls and benign diseases group. Circulating CCNB2 mRNA level was significantly (p<0.001) correlated with cancer stage and metastasis status. Receiver operating characteristic (ROC) analysis showed an area under the curve (AUC) of 0.87 and 0.83 (p<0.05) in identifying cancer patients' metastasis status in lung and digestive tract cancer, respectively. Moreover, we observed that expression levels of circulating CCNB2 mRNA in cancer patients significantly decreased (p=0.0084) after their therapeutic treatments. These data suggest that detection of serum circulating CCNB2 mRNA may have potential clinical applications in screening and monitoring of metastasis and therapeutic treatments.

Use of serum circulating CCNB2 in cancer surveillance.

Cyclin B2 (CCNB2), a member of the cyclin protein family, has been found to be up-regulated in human cancers. To evaluate the potential use of circulating CCNB2 in serum in cancer surveillance, we examined relative expression levels of serum circulating CCNB2 mRNA in 103 cancer patients, 19 normal controls, and 40 benign disease patients using real-time quantitative reverse transcriptase polymerase chain reaction. We found that the relative expression level of circulating CCNB2 mRNA in cancer patients was significantly higher (p<0.0001) than that in normal controls and benign diseases group. Circulating CCNB2 mRNA level was significantly (p<0.001) correlated with cancer stage and metastasis status. Receiver operating characteristic (ROC) analysis showed an area under the curve (AUC) of 0.87 and 0.83 (p<0.05) in identifying cancer patients' metastasis status in lung and digestive tract cancer, respectively. Moreover, we observed that expression levels of circulating CCNB2 mRNA in cancer patients significantly decreased (p=0.0084) after their therapeutic treatments. These data suggest that detection of serum circulating CCNB2 mRNA may have potential clinical applications in screening and monitoring of metastasis and therapeutic treatments.

[Curative effects of FTQ combined with cisplatin in treatment of advanced gastric cancer: a multicenter study].

OBJECTIVE: To determine the clinical toxicities and antitumor effects of a chemotherapy regimen of FTQ, a compound preparation of tegafur, the drug prototype of 5-furacil (5-FU), gimeracil (CDHP), a decomposition inhibitor of 5-FU, oteracil potassium, phosphorylation inhibitor of 5-FU, and combined with cisplatin in patients with inoperable locally or metastatic advanced gastric cancer. METHODS: 119 patients with inoperable locally or metastatic advanced gastric cancer admitted in 10 hospitals in China were divided into 2 groups: FTQ group (n = 59), undergoing a 3-week regime, i.e. oral use of 80 mg x m(-2) x d(-1) for 14 d and then discontinuance for 1 week and intravenous drip cisplatin 75 mg/m2 on days 1-3; and control group (n = 60) undergoing a 3-week regimen including oral use of tegafur 800 mg x m(-2) x d(-1) tid for 14 d and then discontinuance for 1 week and intravenous drip of cisplatin 75 mg/m2 on days 1-3. The curative was evaluated after at least after 2 regimens. RESULTS: There were 102 patients in the per-protocol population. The overall response rate of the FTQ group was 28. 3% (15/53), significantly higher than that of the control group (4.1%, 2/49, P = 0.004). The clinical improvement of the FTQ group was 50.9%, significantly higher than that of the control group (24.5%, P = 0.006). The main toxicities occurred in bone marrow and the digestive tract. The leucopenia and thrombocytopenia rates of the FTQ group were 47.45% and 32.22% respectively, both similar to those of the control group. There were no differences in the incidence rate of digestive canal side reaction between these 2 groups . CONCLUSION: The regimen of FTQ combined with cisplatin is generally well-tolerated and has substantial antitumor activity.