miR-135b reverses chemoresistance of non-small cell lung cancer cells by downregulation of FZD1.

BACKGROUND: Non-small cell lung cancer (NSCLC) chemoresistance usually limits the clinical efficacy of chemotherapeutic approaches. However, few reports have revealed the regulation of miR-135b and Frizzled-1 (FZD1) involved in NSCLC chemoresistance. METHODS: To identify the mechanism of miR-135b and FZD1 in NSCLC chemoresistance and to observe their biological functions, we detected the expression levels of miR-135b and FZD1 by conducting quantitative real-time polymerase chain reaction (RT-qPCR) and modified the expressions of miR-135b and FZD1 by transiently transfecting cells with miR-135b mimics or FZD1-siRNA. The 3'-untranslated region (3'-UTR) of FZD1 combined with miR-135b was verified through dual-luciferase reporter assay. RESULTS: Compared with that in A549 parental cell lines, the miR-135b expression in drug-resistant lung cancer cell lines (A549/DDP) was decreased and their FZD1 expression was increased. The increased miR-135b expression and silenced FZD1 expression enhanced the sensitivity of resistant cells to cisplatin treatment. The high expression of miR-135b in A549/DDP cells remarkably decreased the mRNA levels of FZD1. FZD1 was further identified as the functional downstream target of miR-135b by directly targeting the 3'-UTR of FZD1. CONCLUSION: The amplification of miR-135b suppressed NSCLC chemoresistance by directly mediating the FZD1 downregulation.

LATS2 as a poor prognostic marker regulates non-small cell lung cancer invasion by modulating MMPs expression.

Large tumor suppressor 2 (LATS2) plays significant roles in tumorigenesis and cancer progression. This study was aimed to analyze the correlation between LATS2 expression and clinicopathologic features and its prognostic significance in non-small cell lung cancer (NSCLC). LATS2 expression was examined in 73 NSCLC clinical specimens and 22 normal lung tissues using immunohistochemistry. Low levels of LATS2 protein were inversely associated with the T classification (P=0.001), N classification (P=0.005) and clinical stage (P=0.001) in NSCLC patients. Patients with lower LATS2 expression had a significantly shorter overall survival than patients with high LATS2 expression. Multivariate analysis suggested that low expression of LATS2 was an independent prognostic indicator (P=0.002) for the survival of patients with NSCLC. Furthermore, overexpression of LATS2 resulted in mobility inhibition in NSCLC cell lines A549 and H1299, and reduced protein level of matrix metalloproteinase-2 (MMP-2) and MMP-9. On the contrary, LATS2 siRNA treatment enhanced cell mobility and increased MMP-2 and MMP-9 protein expression level. In conclusion, low expression of LATS2 is a potential unfavorable prognostic factor and promoted cell invasion and migration in NSCLC.

Down-regulation of miR-133a as a poor prognosticator in non-small cell lung cancer.

miR-133a has been demonstrated to play an important role in tumor progression. The aim of present study was to analyze the correlation between miR-133a expression level and clinicopathologic features and its prognostic significance in non-small cell lung cancer (NSCLC). The expression of miR-133a in 104 pairs of human lung cancer tissues and adjacent normal lung tissues were analyzed by qRT-PCR. Here we show that miR-133a was down-regulated in NSCLC. The levels of miR-133a were negatively correlated with the status of N classification (N0-N1 vs. N2-N3, P=0.000), clinical stage (I-II vs. III-IV, P=0.010) and MMP-14 expression (High vs. Low, P=0.012). The patients with low miR-133a expression had shorter survival time than those with high miR-133a expression. Multivariate analysis indicated that the level of miR-133a expression was an independent prognostic indicator (P=0.012) for the survival of patients with NSCLC. In conclusion, decreased expression of miR-133a might be a potential unfavorable prognostic factor for patients with NSCLC, and further studies would be needed to prove our findings.

Controversies regarding T status and N status for non-small cell lung cancer.

According to the newest version of NCCN Clinical Practice Guidelines for Non-Small Cell Lung Cancer (NSCLC), increasing attentions are paid to the role of nodal status and other high-risk factors, including vascular invasion, wedge resection, tumors > 4 cm, visceral pleural involvement, and incomplete lymph node sampling in the individual clinical treatment. Precise definitions of T status and N status, closely associated with prognosis and treatment, are worth expanding further. However, complexity arises because no unity definition exists regarding individual T and N descriptors. In an attempt to explore the potential prognostic values of the T status and N status, we systematically review relevant literature and found that there still remained some disputes about the definitions and prognosis. The adjacent lobe invasion regarded as T2 or T3 has not been reached consensus yet so far. Lymph node spread patterns are associated with the treatment strategies of NSCLC. This review mainly focus on the role of T status and N status and tried to seek appropriate and individual treatment strategies in NSCLC.

[MiR-373-3p Promotes Invasion and Metastasis of Lung Adenocarcinoma Cells].

BACKGROUND AND OBJECTIVE: Lung cancer is the leading cause of cancer-related deaths worldwide, and metastasis is the major cause of death in lung cancer patients. MiR-373 is closely associated with invasion and metastasis in other tumor cells. This study explored the expression of miR-373-3p in non-small cell lung cancer (NSCLC) and its effect on the invasive and metastatic capabilities of lung adenocarcinoma cells, as well as their mechanisms of action. METHODS: The expression of miR-373-3p in NSCLC tissues and lung adenocarcinoma cell lines was detected by quantitative reverse transcription polymerase chain reaction. The roles of miR-373-3p in regulating lung adenocarcinoma cell invasion and metastatic properties were analyzed with miR-373-3p mimic/inhibitor-transfected cells via Transwell chamber assay. Matrix metalloproteinase MMP-9 and MMP-14 protein levels were detected by Western blot in lung cancer cells after transfection. RESULTS: MiR-373-3p was upregulated in 51 NSCLC tissues and 5 NSCLC cell lines. Gain-of-function and loss-of-function studies showed that overexpression of miR-373-3p promoted H1299 cell migration and invasion, which resulted in upregulation of MMP-9 and MMP-14. By contrast, miR-373-3p knockdown inhibited these processes in A549 cells and downregulated the expression of MMP-9 and MMP-14. CONCLUSIONS: Our results demonstrated that miR-373-3p participated in the invasion and metastasis of lung adenocarcinoma cells, partly by upregulation of MMP-9 and MMP-14.

Let-7a inhibits migration, invasion and epithelial-mesenchymal transition by targeting HMGA2 in nasopharyngeal carcinoma.

BACKGROUND: Let-7a has been shown to play important roles in nasopharyngeal carcinoma (NPC) cell proliferation and apoptosis, but little is known about the function and mechanism of let-7a in nasopharyngeal carcinoma metastasis. We aimed to investigate the function and mechanism of let-7a in nasopharyngeal carcinoma metastasis and clarified the regulation of high mobility group A2 (HMGA2) by let-7a. METHODS: The expression levels of let-7a and HMGA2 were examined in NPC clinical specimens using quantitative reverse transcription-PCR (RT-qPCR). HMGA2 was confirmed as a target of let-7a through luciferase reporter assays, RT-qPCR, and Western blotting. Furthermore, the roles of let-7a and HMGA2 in regulating NPC cells biological properties including proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process were analyzed with let-7a mimics and si-HMGA2 transfected cells. RESULTS: Our study demonstrated that let-7a was downregulated and inversely associated with the clinical stage, T classification and N classification, and HMGA2 was upregulated and directly associated with the clinical stage and N classification in patients with NPC. Moreover, there was an inverse correlation between let-7a expression and HMGA2 expression in NPC patient. In addition, HMGA2 was negatively regulated at the posttranscriptional level by let-7a via a binding site of HMGA2-3'UTR. In addition, synthetic let-7a mimics suppressed NPC cells migration, invasion and EMT process and knockdown of HMGA2 was consistent with the effects of let-7a in NPC cells. CONCLUSION: Let-7a directly downregulates HMGA2 protein expression, which suppress NPC cell migration, invasion and EMT process. Let-7a could serve as a potential diagnostic marker and therapeutic target for NPC.

Clinical efficacy of preoperative chemotherapy with or without ifosfamide in patients with osteosarcoma of the extremity: meta-analysis of randomized controlled trials.

Ifosfamide has been used in neoadjuvant chemotherapy since the mid-1980s. Although several studies have been conducted, the results remain controversial. Randomized controlled trials have an improved balance of confounding factors and reliable results. Thus, we performed a meta-analysis based on randomized controlled trials to gather more evidence of the effect of ifosfamide on neoadjuvant chemotherapy for patients with osteosarcoma of the extremity. An electronic search was conducted via the Internet retrieval system to identify eligible trials until September 2014. Odds ratios (ORs) and 95 % confidence interval (CI) were calculated to compare the results of ifosfamide and ifosfamide-free therapies. Four trials with a total of 1,378 patients were eligible for our meta-analysis. Overall, compared with neoadjuvant chemotherapy without ifosfamide, the use of ifosfamide had no advantage in terms of histological response to chemotherapy (cHR; OR 1.36; 95 % CI 0.90-2.03, P = 0.140), 5-year event-free survival (EFS; OR 1.16; 95 % CI 0.789-1.75, P = 0.464), and 5-year overall survival (OS; OR 1.06; 95 % CI 0.70-1.59, P = 0.794). However, improvement was noted in the rate of limb salvage (OR 4.06; 95 % CI 2.04-8.10, P < 0.001). Neoadjuvant chemotherapy with ifosfamide for patients with extremity osteosarcoma might not increase the cHR and exhibited no significant effect on either EFS or OS. However, ifosfamide therapy could significantly increase the rate of limb salvage for osteosarcoma of the extremity, which suggests that the preoperative use of ifosfamide could increase the success rate of limb salvage operation.

MMP-14 overexpression correlates with poor prognosis in non-small cell lung cancer.

Matrix metalloproteinase-14 (MMP-14) has been demonstrated to play an important role in tumor progression. The aim of this study was to analyze the correlation between MMP-14 expression and clinicopathologic features and its prognostic significance in non-small cell lung cancer (NSCLC). Immunohistochemical staining for MMP-14 protein was performed in 104 patients with NSCLC. High levels of MMP-14 protein were positively correlated with the status of clinical stage (I-II vs. III-IV; P < 0.001), N classification (N0-N1 vs. N2-N3; P < 0.001), distant metastasis (no vs. yes; P = 0.014), and differentiated degree (high vs. low or undifferentiated; P = 0.001). The patients with higher MMP-14 expression of protein had shorter survival time than patients with low MMP-14 expression. Multivariate analysis indicated that the level of MMP-14 expression was an independent prognostic indicator (P < 0.001) for the survival of patients with NSCLC. In conclusion, MMP-14 is a potential unfavorable prognostic factor for patients with NSCLC.