Yuanda Cheng

MicroRNA-361-3p suppresses tumor cell proliferation and metastasis by directly targeting SH2B1 in NSCLC.

BackgroundLung cancer is the most common malignancies worldwide. However, the detailed molecular mechanisms underlying lung cancer progression are still not completely clear. MicroRNAs are small noncoding RNAs which occupy a crucial role of cancer metastasis. Accumulating evidence suggests that miR-361 plays important roles in human carcinogenesis. However, its precise biological role remains largely elusive, especially in lung cancer. This study examined the role of miR-361-3p in non-small cell lung cancer (NSCLC).MethodsReal-time quantitative PCR (qRT-PCR) was used to analyze the expression of miR-361-3p in NSCLC tissue and in compared adjacent non-cancerous tissues. The effect of miR-361-3p on proliferation was evaluated by CCK8 and colony formation assays. The effect of miR-361-3p on migration and invasion was evaluated by transwell assays. Western blotting and immunohistochemical staining were applied to analyze the expression of target proteins and downstream molecule, and the luciferase reporter assay to assess the target genes of miR-361-3p in non-small cell lung cancer cells.ResultsmiR-361-3p was significantly decreased in NSCLC tissue and cell lines, and its expression levels were highly correlated with lymph node metastasis (P < 0.01) and TNM stages (P < 0.05). Down-regulation of miR-361-3p promoted cell growth, proliferation, colony formation, invasion and migration in vitro, and promoted proliferation and metastasis in vivo (P < 0.01); whereas up-regulation of miR-361-3p had the contrary effects. The luciferase reporter assay showed that SH2B1 was a direct target gene of miR-361-3p. Enforced expression of miR-361-3p inhibited the expression of SH2B1 significantly and the restoration of SH2B1 expression reversed the inhibitory effects of miR-361-3p on NSCLC cell proliferation and metastasis.ConclusionsmiR-361-3p functions as a novel tumor suppressor in NSCLC and the anti-oncogenic activity may involve its inhibition of the target gene SH2B1. These findings suggest the possibility for miR-361-3p as a therapeutic target in NSCLC.

Clinical controlled comparison between lobectomy and segmental resection for patients over 70 years of age with clinical stage I non-small cell lung cancer

AIMS The standard surgical procedure for elderly (≥ 70 years) patients with clinical stage I non-small cell lung cancer (NSCLC) was investigated. METHODS A non-randomized prospective controlled study was conducted to compare lobectomy with segmental resection for the treatment of elderly clinical stage I lung cancer patients under different pulmonary function. Perioperative indicators including time and volume of thoracic drainage, incidence of postoperative complications, locoregional recurrence rates, and 1, 3, and 5-year survival rates were analyzed. RESULTS A total of 184 patients were included in the study. Patients were classified into two groups according to pulmonary function: group 1 included 64 patients who had poor pulmonary function, with a forced expiratory volume in 1 s (FEV(1)) of less than 1.5 L, whereas group 2 consisted of 120 patients with an FEV(1) ≥ 1.5 L. The patients in group 1 had a longer postoperative mechanical ventilation time and a higher incidence rate of respiratory associated complications than those in group 2 (21.9 vs. 8.35%, p = 0.009). The local recurrence and long-term survival rates were not significantly different between lobectomy and segmental resection. Among the patients who underwent segmental resection, those who had regional lymph node dissection showed a higher 3-year and 5-year survival rate than those undergoing selected lymph node resection (77.8 vs. 51.7%, p = 0.042; 55.6 vs. 27.6%, p = 0.034), but this was not significant in lobectomy. CONCLUSIONS Segmental resection combined with regional lymph node resection could be the best choice for elderly clinical stage I NSCLC patients with FEV(1) < 1.5 L.

miR-675-5p enhances tumorigenesis and metastasis of esophageal squamous cell carcinoma by targeting REPS2

Recently H19 has been demonstrated to be up-regulated in esophageal squamous cell carcinoma (ESCC) and shown to be the precursor of miR-675 that encodes miR-675-5p conservatively. miR-675 is overexpressed in many human cancers; however, the function of miR-675-5p is largely unknown in ESCC. In this study, we found that miR-675-5p expression was significantly increased in ESCC tissues and cell lines and related with ESCC progression and poor prognosis. We also showed here that down-regulation of miR-675-5p in ESCC cells dramatically induced cell G1 arrest and reduced cell proliferation, colony formation, migration and invasion in vitro as well as tumorigenesis and tumor metastasis in vivo. We subsequently identified that REPS2 was a target gene of miR-675-5p. We found that inhibition of miR-675-5p up-regulated the expression of REPS2, inhibited RalBP1/RAC1/CDC42 signaling pathway. Inversely, interference of REPS2 abrogated the effect induced by miR-675-5p inhibition, which resembled the function of miR-675-5p up-regulation. Taken together, our findings suggested that miR-675-5p might play an oncogenic role in ESCC through RalBP1/RAC1/CDC42 signaling pathway by inhibiting REPS2 and might serve as a valuable prognostic biomarker and therapeutic target for ESCC patients.

PRKAR1A is a functional tumor suppressor inhibiting ERK/Snail/E-cadherin pathway in lung adenocarcinoma

Protein Kinase cAMP-Dependent Regulatory Type I Alpha (PRKAR1A) is a tissue-specific extinguisher that transduces a signal through phosphorylation of different target proteins. Loss of PRKAR1A was frequently observed in endocrine neoplasia and stromal cell tumors. However, a few cases were seen in epithelial tumors. Previously, we first found that PRKAR1A was downregulated in lung adenocarcinoma patients. Thus, the present study aimed to clarify its clinical implication and biological function as a tumor suppressor in lung adenocarcinoma. The low levels of PRKAR1A transcript were correlated with tumor progression and poor overall survival. The re-expression of PRKAR1A in H1299 cells suppressed the tumor cell proliferation and migration; stable knockdown (KD) of PRKAR1A in A549 cells enhanced this function both in vitro and in vivo. Moreover, KD of PRKAR1A in A549 cells promoted the statistical colonization of circulating tumor cells to the lungs in nude mice. These effects by PRKAR1A were attributed to inhibiting E-cadherin expression. Elevated E-cadherin significantly suppressed the PRKAR1A-KD induced cell proliferation and migration. Most notably, deletion of PRKAR1A inhibited E-cadherin by activating ERK/Snail signaling. In conclusion, PRKAR1A was a potent suppressor, and through the inhibition of PRKAR1A-ERK-Snail-E-cadherin axis could serve as a potential therapeutic target.

Video-assisted versus conventional thoracotomy pneumonectomy: a comparison of perioperative outcomes and short-term measures of convalescence

BACKGROUND Pneumonectomy is a proven treatment for lung diseases. We sought to present a comparison between video-assisted thoracic surgery pneumonectomy (VATS-P) and conventional thoracotomy pneumonectomy (CP) on perioperative outcomes and short-term measures of convalescence. METHODS A retrospective cohort study was performed to assess perioperative outcomes among patients underwent VATS-P and CP. A total of 32 patients undergoing VATS-P were matched 2:1 about comorbidity, surgical indication, tumour size and lesion location to a previous cohort of 64 patients who underwent CP. Demographic and perioperative data were obtained. Statistical analysis was performed. RESULTS Mean patient age was 55.4 years for both groups, with equal sex distribution. Pneumonectomy for malignant and benign lesion patients was evaluated individually. For malignant tumour patients, median tumour size was 3.9 cm for both groups. There was no difference between VATS-P and CP cases in transfusion rates (2% vs. 10%, P=0.50), dissected lymph node numbers (11.9 vs. 14.2, P=0.26), dissected lymph node stations (5.0 vs. 4.9, P=0.75), estimated blood loss (226.0 vs. 261.3 mL, P=0.40), complication rate (20.0% vs. 22.5%, P=0.82), postoperative drainage time (5.9 vs. 6.2, P=0.50) or length of hospital stay (7.5 vs. 8.1, P=0.50). Operation time in VATS-P was higher than conventional groups (187.5 vs. 146.3 min, P=0.00) but the mean pain score was significantly less. For benign patients, over 1,000 mL blood losing (1,033.3 vs. 1,233.3 mL, P=0.78) and 180 minutes (186.6 vs. 105.8, P=0.73) OR time was found in both groups. The Length of stay (7.6 vs. 6.3 d, P=0.57), transfusion rates (66.7% vs. 33.3%), complications rates (zero in both group) and length of drainage (6.7 vs. 6.7 d, P=1.0) between two groups are identical. CONCLUSIONS Complete video-assisted thoracic surgery (VATS) pneumonectomy is feasible and safe technique and can be recommended as a surgical treatment for lung cancer patients. However, long-term benefits need to be evaluated by further studies and large sample tests.

Genome-wide analyses of long noncoding RNA expression profiles in lung adenocarcinoma

LncRNAs have emerged as a novel class of critical regulators of cancer. We aimed to construct a landscape of lncRNAs and their potential target genes in lung adenocarcinoma. Genome-wide expression of lncRNAs and mRNAs was determined using microarray. qRT-PCR was performed to validate the expression of the selected lncRNAs in a cohort of 42 tumor tissues and adjacent normal tissues. R and Bioconductor were used for data analysis. A total of 3045 lncRNAs were differentially expressed between the paired tumor and normal tissues (1048 up and 1997 down). Meanwhile, our data showed that the expression NONHSAT077036 was associated with N classification and clinical stage. Further, we analyzed the potential co-regulatory relationship between the lncRNAs and their potential target genes using the ‘cis’ and ‘trans’ models. In the 25 related transcription factors (TFs), our analysis of The Cancer Genome Atlas database (TCGA) found that patients with lower expression of POU2F2 and higher expression of TRIM28 had a shorter overall survival time. The POU2F2 and TRIM28 co-expressed lncRNA landscape characterized here may shed light into normal biology and lung adenocarcinoma pathogenesis, and be valuable for discovery of biomarkers.

SH2B1 promotes epithelial-mesenchymal transition through the IRS1/β-catenin signaling axis in lung adenocarcinoma

Lung adenocarcinoma (LADC), the most prevalent type of human lung cancer, is characterized by many molecular abnormalities. SH2B1, a member of the SH2‐domain containing family, have recently been shown to act as tumor activators in multiple cancers, including LADC. However, the mechanisms underlying SH2B1 overexpression are not completely understood. Here, we reported that SH2B1 expression levels were significantly upregulated and positively associated with EMT markers and poor patient survival in LADC specimens. Modulation of SH2B1 levels had distinct effects on cell proliferation, cell cycle, migration, invasion, and morphology in A549 and H1299 cells in vitro and in vivo. At the molecular level, overexpression of SH2B1 resulted in the upregulation of the EMT markers, especially induced β‐catenin accumulation and activated β‐catenin signaling to promote LADC cell proliferation and metastasis, while silencing SH2B1 had the opposite effect. Furthermore, ectopic expression of SH2B1 in H1299 cells increased IRS1 expression level. Reduced expression of IRS1 considerably inhibited H1299 cell proliferation, migration, and invasion which were driven by SH2B1 overexpression. Collectively, these results provide unequivocal evidence to establish that SH2B1‐IRS1‐β‐catenin axis is required for promoting EMT, and might prove to be a promising strategy for restraining tumor progression in LADC patients.

Expression and Clinical Significance of REPS2 in Human Esophageal Squamous Cell Carcinoma

OBJECTIVE REPS2 plays important roles in inhibiting cell proliferation, migration and in inducing apoptosis of cancer cells, now being identified as a useful biomarker for favorable prognosis in prostate and breast cancers. The purpose of this study was to assess REPS2 expression and to explore its role in esophageal squamous cell carcinoma (ESCC). METHODS Protein expression of REPS2 in ESCCs and adjacent non-cancerous tissues from 120 patients was analyzed by immunohistochemistry and correlated with clinicopathological parameters and patient outcome. Additionally, thirty paired ESCC tissues and four ESCC cell lines and one normal human esophageal epithelial cell line were evaluated for REPS2 mRNA and protein expression levels by quantitative RT-PCR and Western blotting. RESULTS REPS2 mRNA and protein expression levels were down-regulated in ESCC tissues and cell lines. Low protein levels were significantly associated with primary tumour, TNM stage, lymph node metastasis and recurrence (all, P < 0.05). Survival analysis demonstrated that decreased REPS2 expression was significantly associated with shorter overall survival and disease-free survival (both, P < 0.001), especially in early stage ESCC patients. When REPS2 expression and lymph node metastasis status were combined, patients with low REPS2 expression/lymph node (+) had both poorer overall and disease-free survival than others (both, P < 0.001). Cox multivariate regression analysis further revealed REPS2 to be an independent prognostic factor for ESCC patients. CONCLUSIONS Our findings demonstrate that downregulation of REPS2 may contribute to malignant progression of ESCC and represent a novel prognostic marker and a potential therapeutic target for ESCC patients.

Diagnostic and Prognostic Potential of Circulating Long Non-Coding RNAs in Non Small Cell Lung Cancer

Lung cancer is the leading cause of cancer-related mortality worldwide. Approximately 80% of lung cancer cases are non–small cell lung carcinoma (NSCLC). However current diagnostic and therapeutic modalities against NSCLC are ineffective due to incomplete understanding of molecular pathogenesis of NSCLC. Emerging evidence shows that long non-coding RNAs (lncRNAs) can function as biomarkers for diagnosis and prognosis. LncRNAs can control transcription, translation, and protein function via diverse mechanisms although they lack the protein coding potential. LncRNAs have attracted intense investigations on their roles in cancer. Mounting evidence indicates that lncRNAs are promising biomarkers in diagnosis and prognosis for NSCLC, especially their presence in body fluids. Herein we will review recent advances in the research that explores the diagnostic and prognostic potentials of lncRNAs in NSCLC. We will also discuss emerging evidence that suggested lncRNAs as therapeutic targets in NSCLC.

SH2B1 promotes NSCLC cell proliferation through PI3K/Akt/mTOR signaling cascade

BackgroundNon-small cell lung cancer (NSCLC), the most prevalent type of human lung cancer, is characterized by many molecular abnormalities. SH2B1, a member of the SH2-domain containing family, have recently been shown to act as tumor activators in multiple cancers. The objective of this study was to investigate the role SH2B1 and the underlying molecular mechanism in NSCLC.MethodsCell functional analysis and cell line-derived xenograft model were performed to determine SH2B1 potential roles on NSCLC cell proliferation in vitro and in vivo. In vitro assays were performed to identify signal molecular mechanisms. Subsequently, 104 patients with NSCLC undergoing primary surgical resection were recruited to evaluated expression of SH2B1 and Akt/mTOR signaling markers by immunohistochemical staining to determine their clinicopathologic significance.ResultsModulation of SH2B1 expression levels had distinct effects on cell proliferation, cell cycle and apoptosis in the NSCLC cell lines A549 and H1299. At the molecular level, overexpression of SH2B1 resulted in the upregulation of the Akt/mTOR markers, p-Akt and p-mTOR, and downregulation of PTEN to promote NSCLC cell proliferation, while silencing SH2B1 had the opposite effect. In human NSCLC specimens, SH2B1 expression levels were positively associated with Akt/mTOR signaling pathway markers.ConclusionsThe SH2B1/Akt/mTOR/PTEN axis is required for regulating NSCLC cell proliferation and might prove to be a promising strategy for restraining tumor progression in NSCLC patients.