Jiajun Du

High expression of miR-21 and miR-155 predicts recurrence and unfavourable survival in non-small cell lung cancer.

We synthesised the evidence of microRNAs as prognostic biomarkers in lung cancer. Studies were identified by searching PubMed, Embase and Web of Science until March 2012. Descriptive characteristics for studies were described and an additional meta-analysis for two specific microRNAs (miR-21 and miR-155) which were studied extensively was performed. Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated. The median study size was 88 patients (interquartile range [IQR]=53-193) and the median HR in the studies that reported statistically significant results was 2.855 (IQR=2.01-5.035). For the studies evaluating miR-21s association with clinical outcomes, the pooled HR suggested that high expression of miR-21 has a negative impact on overall survival (OS) in non-small cell lung cancer (NSCLC) (HR=2.32[1.17-4.62], P<0.05) and recurrence-free survival (RFS)/cancer-specific survival (CSS) in lung adenocarcinoma (HR=2.43[1.67-3.54], P<0.001). As for miR-155, the pooled HR for OS was 2.09 (95%CI: 0.68-6.41, P>0.05) which was not statistically significant, but for RFS/CSS was 1.42 (95% CI: 1.10-1.83, P=0.007). These results indicate that microRNAs show promising associations with prognosis in lung cancer; moreover, specific microRNAs such as miR-21 and miR-155 can predict recurrence and poor survival in NSCLC.

Tumor-Associated Neutrophils as a New Prognostic Factor in Cancer: A Systematic Review and Meta-Analysis

Purpose Tumor-associated neutrophils (TAN) have been reported in a variety of malignancies. We conducted an up-to-date meta-analysis to evaluate the prognostic role of TAN in cancer. Method Pubmed, Embase and web of science databases were searched for studies published up to April 2013. Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated. The impact of neutrophils localization and primary antibody were also assessed. Results A total of 3946 patients with various solid tumors from 20 studies were included. High density of intratumoral neutrophils were independently associated with unfavorable survival; the pooled HRs were 1.68 (95%CI: 1.36–2.07, I2 = 55.8%, p<0.001) for recurrence-free survival (RFS)/disease-free survival (DFS), 3.36 (95%CI: 2.08–5.42, I2 = 0%, p<0.001) for cancer-specific survival (CSS) and 1.66 (95%CI: 1.37–2.01, I2 = 70.5%, p<0.001) for overall survival (OS). Peritumoral and stromal neutrophils were not statistically significantly associated with survival. When grouped by primary antibody, the pooled HRs were 1.80 (95%CI: 1.47–2.22, I2 = 67.7%, p<0.001) for CD66b, and 1.44 (95%CI: 0.90–2.30, I2 = 45.9%, p = 0.125) for CD15, suggesting that CD66b positive TAN might have a better prognostic value than CD15. Conclusion High levels of intratumoral neutrophils are associated with unfavorable recurrence-free, cancer-specific and overall survival.

Prognostic Significance of Systemic Inflammation-Based Lymphocyte- Monocyte Ratio in Patients with Lung Cancer: Based on a Large Cohort Study

Increasing evidence indicates cancer-related inflammatory biomarkers show great promise for predicting the outcome of cancer patients. The lymphocyte- monocyte ratio (LMR) was demonstrated to be independent prognostic factor mainly in hematologic tumor. The aim of the present study was to investigate the prognostic value of LMR in operable lung cancer. We retrospectively enrolled a large cohort of patients with primary lung cancer who underwent complete resection at our institution from 2006 to 2011. Inflammatory biomarkers including lymphocyte count and monocyte count were collected from routinely performed preoperative blood tests and the LMR was calculated. Survival analyses were calculated for overall survival (OS) and disease-free survival (DFS). A total of 1453 patients were enrolled in the study. The LMR was significantly associated with OS and DFS in multivariate analyses of the whole cohort (HR = 1.522, 95% CI: 1.275–1.816 for OS, and HR = 1.338, 95% CI: 1.152–1.556 for DFS). Univariate subgroup analyses disclosed that the prognostic value was limited to patients with non-small-cell lung cancer (NSCLC) (HR: 1.824, 95% CI: 1.520–2.190), in contrast to patients with small cell lung cancer (HR: 1.718, 95% CI: 0.946–3.122). Multivariate analyses demonstrated that LMR was still an independent prognostic factor in NSCLC. LMR can be considered as a useful independent prognostic marker in patients with NSCLC after complete resection. This will provide a reliable and convenient biomarker to stratify high risk of death in patients with operable NSCLC.

MicroRNA-143 functions as a tumor suppressor in human esophageal squamous cell carcinoma

Esophageal cancer is one of the most common cancers worldwide with a poor prognosis. MicroRNAs(miRNAs) are a class of naturally occurring small noncoding RNAs and play an important role in cancer initiation and development. In this study, we demonstrate that the expression levels of miR-143 and miR-145 were significantly decreased in ESCC tissues in comparison with adjacent normal esophageal squamous tissues(NESTs). Furthermore, an inverse correlation between miR-143 and tumor invasion depth and lymph node metastasis was observed. The enforced expression of miR-143 induced growth suppression and apoptosis of ESCC cells. Rescue of miR-143 significantly suppressed the ESCC cells migration and invasion capabilities. Moreover, we show that functions of miR-143 in ESCC are mediated at least in part by the inhibition of extracellular signal regulated kinase-5(ERK-5) activity. These results prove that miR-143 may act as a tumor suppressor in ESCC.

MicroRNA-34b functions as a tumor suppressor and acts as a nodal point in the feedback loop with Met.

MicroRNAs (miRNAs), as a class of naturally occurring small non-coding RNAs, play profound and pervasive roles in cancer initiation and progression. Extensive decrease in miRNA levels are frequently observed in human cancers, indicating that miRNAs may function intrinsically in tumor suppression. However, the underlying mechanisms of miRNA interactions with cellular pathways are still unclear. The expression of miR-34b in non-small cell lung cancer (NSCLC) tissues was detected using quantitative real-time PCR. The relations between miR-34b expression levels and pathological stage or lymph node metastasis were assessed using the Spearman correlation test. For in vitro studies, lung cancer cells were transfected with double stranded synthetic miRNA mimics (syn-hsa-miR-34b miScript miRNA) and scrambled controls. Immunohistochemistry was used to validate the related downstream proteins of miR-34b. The expression of miR-34b was lower in NSCLC tissues compared to that in pericarcinous tissues of lung cancer. Additionally, the Spearman correlation test showed that lower miR-34b expression was correlated with higher lymph node metastasis. In vitro gain-of-function experiments indicated that miR-34b suppressed cell proliferation by inducing cell apoptosis. IHC results showed association between lower miR-34b and overexpression of phospho-Met, p53 (phospho S392) and Mdm2. Consistent with the opposing correlation between the expression of miR-34b and lymph node metastasis in NSCLC, miR-34b may play an important role in NSCLC progression. Furthermore, miR-34b downregulates Met, with subsequent changes of downstream p53 (phospho S392) and Mdm2, and inversely p53 upregulates miR-34b in a feedback loop, which provides new insights into the roles of miR-34 family members in the regulation of signaling pathways of NSCLC.

A comparison of Twist and E-cadherin protein expression in primary non-small-cell lung carcinoma and corresponding metastases §

OBJECTIVE The metastasis of solid tumors is directly or indirectly responsible for most cancer-related deaths. It has already been known that in non-small-cell lung carcinoma cells, up-regulation of Twist (a highly conserved basic helix-loop-helix transcription factor) can promote epithelial-mesenchymal transition through down-regulation of E-cadherin. The main aim of this study was to determine whether the expression of Twist and E-cadherin differs between primary and metastatic lung carcinoma and to correlate Twist and E-cadherin expression in primary and metastatic non-small-cell lung carcinoma. METHODS Thirteen patients with non-small-cell lung carcinoma and hematogenous metastases were studied in retrospect, and Twist and E-cadherin were detected by immunohistochemistry in 26 tissue samples from the 13 patients. RESULTS We demonstrated that the expression of Twist was higher in metastatic non-small-cell lung carcinoma tissues than in primary non-small-cell lung carcinoma (p=0.008) and discordance of Twist expression was observed in 11 (85%) patients. For E-cadherin, 12 cases (92%) showed discordance between primary tumor and metastasis (p=0.002): E-cadherin expressed higher in the primary tumor than in the metastasis in 12 cases. We also found that increased Twist expression was correlated with decreased membranous E-cadherin expression (p=0.009). CONCLUSIONS Our data imply that Twist induces epithelial-mesenchymal transition in non-small-cell lung carcinoma by reducing E-cadherin, then promoting metastasis.

Association between Circulating Levels of IGF-1 and IGFBP-3 and Lung Cancer Risk: A Meta-Analysis

Background The insulin-like growth factor (IGF) system was documented to play a predominant role in neoplasia. As lung cancer is one of the most malignant cancers, we conducted a meta-analysis in order to investigate the strength of association between circulating IGF-1 and IGFBP-3 levels and lung cancer. Methodology/Principal Findings A systematic literature search was conducted to identify all prospective case-control studies and case-control studies on circulating IGFs and IGFBPs levels. Six nested case-control studies (1 043 case subjects and 11 472 control participants) and eight case-control studies (401 case subjects and 343 control participants) were included in this meta-analysis. Pooled measure was calculated as the inverse variance-weighted mean of the natural logarithm of multivariate adjusted OR with 95% CIs for highest vs. lowest levels to assess the association of circulating IGF-1 and IGFBP-3 concentrations and lung cancer. Standard mean difference (SMD) was also calculated to indicate the difference of the circulating IGF-1 and IGFBP-3 concentrations between the lung cancer case group and the control group. Of the nested case-control studies, ORs for the highest vs. lowest levels of IGF-1 and IGFBP-3 were 1.047 (95% CI: [0.802,1.367], P = 0.736) and 0.960 (95%CI: [0.591,1.559], P = 0.868) respectively; and SMDs were −0.079 (95%CI:[ −0.169, 0.011], P = 0.086) and −0.097 (95%CI:[ −0.264,0.071], P = 0.258) for IGF-1 and IGFBP-3 respectively. As to the case-control studies, SMDs were 0.568 (95%CI:[ −0.035, 1.171], P = 0.065) and −0.780 (95%CI:[ −1.358, −0.201], P = 0.008) for IGF-1 and IGFBP-3 respectively. Conclusions/Significance Inverse association was shown between IGFBP-3 and lung cancer in the case-control studies,and the circulating level of IGFBP-3 underwent a decline during tumorogenesis and development of lung cancer, which suggested IGFBP-3 a promising candidate for the biomarker of lung cancer.

Prognostic role of Twist or Snail in various carcinomas: a systematic review and meta-analysis

Twist and Snail are considered as key transcriptional repressors of E‐cadherin tightly related to epithelial‐to‐mesenchymal transition (EMT) and cancer progression. Numerous studies have investigated the prognostic value of Twist and Snail. However, the published results were controversial or even opposite. Our article aimed to evaluate the prognostic role of Twist and Snail in patients with cancer.

The analysis of microRNA-34 family expression in human cancer studies comparing cancer tissues with corresponding pericarcinous tissues.

Recently many studies have focused on the microRNA-34 (miR-34) family expression in various cancers; nevertheless, the controversial results of these studies still exist in identifying miR-34 members as new biomarkers of cancers. Therefore, we carried out this comprehensive meta-analysis of published studies that compared the miR-34 family expression profiles between cancer tissues and paired neighboring noncancerous tissues to systemically evaluate the findings globally and address the inconsistencies of pertinent literatures. The data included in this article were collected from Embase, PubMed and Web of Science up to December 2013. To overcome the difficulties that many raw data were unavailable and study methods were different, a vote-counting strategy was adopted to identify consistent markers in our analysis. Ultimately, a total of 23 cancers were reported in the 61 eligible studies, of which 46 studies provided fold-change value information. In the consistently reported cancer types, non-small cell lung cancer (NSCLC), glioma and nasopharyngeal carcinoma (NPC) ranked at the top with down-regulated feature. Cervical neoplasm was consistently reported to be over-expressed in the panel of each member of miR-34s. Subgroup analysis of miR-34 family expression demonstrated that colorectal cancer (CRC), gastric cancer (GC), hepatocellular carcinoma (HCC) and prostate cancer (PCa) were most frequently reported with inconsistent regulations. Our meta-analysis showed that miR-34 family members could be expected to become potential diagnostic and prognostic biomarkers in some types of human cancers. Further well-designed and larger sample studies are surely warranted to identify the role of the miR-34 family in the occurrence and development of tumors.

Administration of embryonic stem cells generates effective antitumor immunity in mice with minor and heavy tumor load

The history of immunizing animals with fetal tissues to generate an antitumor response dates back a century ago. Subsequent reports supported the idea that vaccination with embryonic materials could generate cancer-specific immunity and protect animals from transplantable and chemically induced tumors. In our study, we found C57 BL/6 mice vaccinated with embryonic stem cells (ESCs) received obvious antitumor immunity, which protected them from the formation and development of lung cancer. Furthermore, we investigated the antitumor effects of administration of ESCs in mice with minor and/or heavy tumor load. The tumor growth was monitored, the proliferation of lymphocytes and secretion of cytokines were examined, and finally the tissue sections were approached by immunohistochemical and apoptosis staining. The results suggested that mice injected with ESCs received obvious tumor inhibition and retardation due to significant lymphocyte proliferation and cytokine secretion, which help to rebuild the host’s immunity against cancer to some extent and comprise the main part of antitumor immunity. Moreover, mice with minor tumor load received stronger antitumor effect compared with mice with heavy tumor load, may be due to relatively intact immune system. Thus, besides their function as prophylactic vaccines, administration of ESCs could be a potential treatment for cancer, which obviously prevent and control the proliferation and development of malignant tumors.