[Show abstract][Hide abstract] ABSTRACT: Recently, microRNA-99 family members, such as miR-99a/b and miR-100, have been reported to exhibit abnormal expression in various malignant tumors, but their functions in carcinomas are controversial. In this study, we focused on miR-99a and miR-100, which were determined to be universally downregulated in esophageal squamous cell carcinoma, and investigated their functions and potential mechanisms of action. The downregulation of miR-99a/100 was validated by qRT-PCR in 101 ESCC surgical tissue samples and in 3 ESCC cell lines. The overexpression of miR-99a and miR-100 via the transient transfection of the corresponding precursor molecules inhibited cell proliferation by inducing apoptosis in the ESCC cell lines. To investigate the molecular mechanism of miR-99a/100-induced apoptosis, luciferase reporter assays and Western blots were performed to demonstrate that the overexpression of miR-99a/100 suppressed the expression of mTOR by directly targeting its 3'UTR in a post-transcriptional manner. Clinically, the decreased expression of miR-99a/100 was associated with worse overall survival in ESCC patients. In conclusion, these results indicated that miR-99a and miR-100 inhibited cell proliferation by suppressing mTOR in ESCC cell lines, and therefore, the miR-99a/100-mTOR signaling pathway is a potential therapeutic target for inducing apoptosis to combat ESCC.
Medical Oncology 03/2013; 30(1):411. DOI:10.1007/s12032-012-0411-9 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MicroRNAs (miRNAs) as a species of small non coding single stranded RNA of about 21-25 nucleotides have important roles in the development of different cancers. In present study, we found that the expression of miR-25 was up-regulated in 60 esophageal squamous cell carcinoma (ESCC) tissues compared with matched adjacent non-cancer tissues. Moreover, we demonstrated that the up-regulation of miR-25 was significantly correlated with the status of lymph node metastasis and TNM (Tumor, Node and Metastasis) stage. Furthermore, over-expression of miR-25 markedly promoted migration and invasion of ESCC cells. On the contrary, down-regulation of miR-25 inhibited the migration and invasion of cells. E-cadherin(CDH1) is a very important tumor metastasis suppressor. We further identified that miR-25 directly targeted CDH1 3'-untranslated region (3'UTR) and repressed the expression of CDH1. These results, for the first time, demonstrate that miR-25 promotes ESCC cell migration and invasion by suppressing CDH1 expression.
Biochemical and Biophysical Research Communications 03/2012; 421(4):640-5. DOI:10.1016/j.bbrc.2012.03.048 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction: Smoking and non-smoking lung cancer have many differences in clinical feature. But those may be the result of interference due to differences in pathological type, as most smoking patients suffer squmous cell lung cancer and non-smokings tend to get adenocarcinoma. This study was conducted on the specific histological type—lung ade-nocarcinoma—to avoid histological bias and to reveal the true effect of smoking. Methods: A total of 2222 patients with lung adenocarcinoma confirmed by histological or cytological evidence were enrolled from January 1, 1999 to December 31, 2004. Differences in clinical features and prognosis between non-smoking and smoking patients were analyzed. Chi-square test was used for univariate comparisons. Univariate probability of survival was computed using Kaplan-Meier estimate and compared to using the log-rank test. Cox proportional hazards regression analysis was used to evaluate the risk of death. Results: There were 777 current smokers (34.96%), 197 former smokers (8.87%) and 1248 non-smoking patients (56.17%). 860 non-smoking patients (68.91%) were female, compared with 6.31% among current smokers and 4.06% among former smokers (p < 0.001). Non-smoking patients had an earlier age at diagnosis (p < 0.001) and a better response to chemotherapy (p < 0.001) compared to current smoking patients. Current smoking correlated with lower cell differentiation (p < 0.001) and worse prognosis (p = 0.0024). After multivariate analysis, smoking was identified as an independent negative prognostic factor (HR, 1.302; 95% CI, 1.011 -1.6780, p = 0.041). No difference in prognosis was observed according to smoking conditions in smoking patients. Conclusions: Signifi-cent differences exist in clinical features and prognosis between non-smoking and smoking lung adenocarcinoma pa-tients. There is a strong evidence that non-smoking lung adenocarcinoma should be regard as different disease.
Journal of Cancer Therapy 01/2012; 03(04). DOI:10.4236/jct.2012.324056
[Show abstract][Hide abstract] ABSTRACT: Lung cancer is the leading cause of cancer-related death in the world. To explore tumor biomarkers for clinical application, two-dimensional fluorescence difference gel electrophoresis and subsequent MALDI-TOF/TOF mass spectrometry were performed to identify proteins differentially expressed in 12 pairs of lung squamous cell tumors and their corresponding normal tissues. A total of 28 nonredundant proteins were identified with significant alteration in lung tumors. The up-regulation of isocitrate dehydrogenase 1 (IDH1), superoxide dismutase 2, 14-3-3ε, and receptor of activated protein kinase C1 and the down-regulation of peroxiredoxin 2 in tumors were validated by RT-PCR and Western blot analysis in independent 15 pairs of samples. Increased IDH1 expression was further verified by the immunohistochemical study in extended 73 squamous cell carcinoma and 64 adenocarcinoma clinical samples. A correlation between IDH1 expression and poor overall survival of non-small cell lung cancer (NSCLC) patients was observed. Furthermore, ELISA analysis showed that the plasma level of IDH1 was significantly elevated in NSCLC patients compared with benign lung disease patients and healthy individuals. In addition, knockdown of IDH1 by RNA interference suppressed the proliferation of NSCLC cell line and decreased the growth of xenograft tumors in vivo. These observations suggested that IDH1, as a protein promoting tumor growth, could be used as a plasma biomarker for diagnosis and a histochemical biomarker for prognosis prediction of NSCLC.
[Show abstract][Hide abstract] ABSTRACT: Recent studies have suggested that microRNA biomarkers could be useful for stratifying lung cancer subtypes, but microRNA signatures varied between different populations. Squamous cell carcinoma (SCC) is one major subtype of lung cancer that urgently needs biomarkers to aid patient management. Here, we undertook the first comprehensive investigation on microRNA in Chinese SCC patients.
MicroRNA expression was measured in cancerous and noncancerous tissue pairs strictly collected from Chinese SCC patients (stages I-III), who had not been treated with chemotherapy or radiotherapy prior to surgery. The molecular targets of proposed microRNA were further examined.
We identified a 5-microRNA classifier (hsa-miR-210, hsa-miR-182, hsa-miR-486-5p, hsa-miR-30a, and hsa-miR-140-3p) that could distinguish SCC from normal lung tissues. The classifier had an accuracy of 94.1% in a training cohort (34 patients) and 96.2% in a test cohort (26 patients). We also showed that high expression of hsa-miR-31 was associated with poor survival in these 60 SCC patients by Kaplan-Meier analysis (P = 0.007), by univariate Cox analysis (P = 0.011), and by multivariate Cox analysis (P = 0.011). This association was independently validated in a separate cohort of 88 SCC patients (P = 0.008, 0.011, and 0.003 in Kaplan-Meier analysis, univariate Cox analysis, and multivariate Cox analysis, respectively). We then determined that the tumor suppressor DICER1 is a target of hsa-miR-31. Expression of hsa-miR-31 in a human lung cancer cell line repressed DICER1 activity but not PPP2R2A or LATS2.
Our results identified a new diagnostic microRNA classifier for SCC among Chinese patients and a new prognostic biomarker, hsa-miR-31.
Clinical Cancer Research 09/2011; 17(21):6802-11. DOI:10.1158/1078-0432.CCR-11-0419 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lung cancer is the leading cause of cancer-related death in the world and approximately 30-40% of patients with stage Ⅰ non-small cell lung cancer (NSCLC) die of recurrent disease. miRNA expression profiles can be diagnostic and prognostic markers of lung cancer. Recently, miR-34 family has been shown to be part of the p53 pathway which is frequently involved in lung cancer, and the expression of miR-34 has been reported to be regulated by DNA methylation. In present study, we investigated the correlation between DNA methylation status of miR-34 family and recurrence of stage Ⅰ NSCLC patients. miR-34a and miR-34b/c promoter methylation status were determined by nested methylation-specific PCR in FFPE tumor tissues from 161 patients of stage Ⅰ NSCLC. Furthermore, mature miR-34b and miR-34c expression were analyzed by qRT-PCR in the same panel tissues. Our results revealed that aberrant DNA methylation of miR-34b/c was correlated with a high probability of recurrence (p = 0.026) and associated with poor overall survival (p = 0.010) and disease-free survival (p = 0.017). No significant association was found for miR-34a methylation. Multivariate analysis showed that promoter hypermethylation of miR-34b/c was an independent prognostic factor of stage Ⅰ NSCLC. Moreover, no significant association between mature miR-34b and miR-34c expression and DNA methylation status was found. In conclusion, we have identified promoter hypermethylation of miR-34b/c as a relatively common event in NSCLC and might be a potential prognostic factor for stage Ⅰ NSCLC.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study is to investigate the impact of positive cancer/lung cancer family history (FH) on clinical features and outcome in non-small cell lung cancer (NSCLC) patients. We analyzed 4,491 NSCLC patients with NSCLC who presented from January 1999-December 2005. Chi-square test and Wilcoxon test were used for univariate comparisons, while Cox Proportional Hazards regression analysis was performed to evaluate the adjusted risk of death. Univariate probability of survival was calculated using Kaplan-Meier estimate and compared using the log-rank test. Of 4,491 patients, 579 patients (12.89%) had positive FH, including 233 patients (5.19%) with FH of lung cancer. Patients with positive lung cancer FH, compared to those with negative FH, were diagnosed at earlier age (57 vs. 60; P < 0.001), presented more cases of adenocarcinoma (58.80 vs. 50.69%; P = 0.016), and at more advanced stage (Stage IIIB/IV 45.74 vs. 36.79%; P < 0.001). These differences were also detected in patients with positive cancer FH. In addition, more females and non-smokers were among patients with positive cancer FH (30.05 vs. 26.15%; P = 0.045 and 39.90 vs. 33.82%; P = 0.008, respectively). Furthermore, patients with advanced cancer (stage IIIB/IV) who had positive FH had lower response rate to chemotherapy (CR&PR 24.68 vs. 34.42%; P = 0.024). Nevertheless, patients with positive lung cancer FH had better prognosis (P = 0.015), especially if diagnosed at an early stage (P = 0.035), and their adjusted relative risk of death was lower (RR 0.69; 95% CI: 0.51-0.93; P = 0.015). Definite epidemiologic and survival differences exist between NSCLC patients with positive or negative FH of cancer. Our results suggest that cancer FH is an important factor of clinical features, and could serve as a prognostic indicator for NSCLC.
Familial Cancer 11/2010; 10(2):331-6. DOI:10.1007/s10689-010-9403-0 · 1.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lung cancer remains the most common cause of death for malignancy in both men and women. Current therapies for NSCLC patients are inefficient due to the lack of diagnostic and therapeutic markers. The phospho-Ser/Thr-Pro specific prolyl-isomerase Pin1 is overexpressed in many different cancers, including NSCLC, and may possibly be used as a target for cancer therapy. We identified 79 cases with the follow-up survival and investigated the clinical relevance of Pin1 expression in NSCLC patients. To validate the oncogenic potential of Pin1 in lung cells, we overexpressed Pin1 in Glc82 cells, and downregulated Pin1 by RNA interference in H1299 cells. The 5-year survival rate of the 79 patients was 54.6%. High expression of Pin1 correlated with poor survival by univariate analysis as well as by multivariate analysis, demonstrating that high expression of Pin1 was an independent prognostic factor. Consistent with the clinical findings, overexpression of Pin1 in Glc82 cells increased cell growth and colony formation and tumorigenicity in nude mice including cell migration, invasion. To further validate the role of Pin1 in lung cancer carcinogenesis, lentivirus-mediated siRNA targeting of Pin1 resulted in the stable suppression of both cell growth, anchorage-independent growth in soft agar and tumorigenic including cell migration, invasion in H1299 cells. Pin1 expression may be an unfavorable prognostic factor in patients of NSCLC patients, and these results indicate that Pin1 may have a role in tumor development and metastasis and thus could serve as a novel target for treatment of NSCLC.
[Show abstract][Hide abstract] ABSTRACT: Increasing evidence has suggested that RhoE plays an important role in carcinogenesis and progression. However, the correlation between RhoE expression and clinical outcome in lung cancer has not been investigated.
RhoE expression was detected by immunohistochemistry on tissue microarray containing samples from 115 patients with non-small cell lung cancer with a median follow-up of 54 months.
RhoE was overexpressed in the cytoplasm of lung cancer cells compared with undetectable expression of RhoE in the adjacent nontumoral cells. Patients with RhoE-negative tumors had substantially longer cancer-related survival than did patients with RhoE-positive tumors. Multivariate analysis showed that RhoE overexpression was an independent marker for cancer-related survival in the entire population after adjusting for other prognostic factors.
RhoE expression may serve as an unfavorable prognostic factor in patients with non-small cell lung cancer.