CA : A Cancer Journal for Clinicians

Epidemiology of Lung Cancer : Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

MicroRNAs (miRNAs) are small non-coding RNAs with a length of about 19–25 nt, which can regulate various target genes and are thus involved in the regulation of a variety of biological and pathological processes, including the formation and development of cancer. Drug resistance in cancer chemotherapy is one of the main obstacles to curing this malignant disease. Statistical data indicate that over 90% of the mortality of patients with cancer is related to drug resistance. Drug resistance of cancer chemotherapy can be caused by many mechanisms, such as decreased antitumor drug uptake, modified drug targets, altered cell cycle checkpoints, or increased DNA damage repair, among others. In recent years, many studies have shown that miRNAs are involved in the drug resistance of tumor cells by targeting drug-resistance-related genes or influencing genes related to cell proliferation, cell cycle, and apoptosis. A single miRNA often targets a number of genes, and its regulatory effect is tissue-specific. In this review, we emphasize the miRNAs that are involved in the regulation of drug resistance among different cancers and probe the mechanisms of the deregulated expression of miRNAs. The molecular targets of miRNAs and their underlying signaling pathways are also explored comprehensively. A holistic understanding of the functions of miRNAs in drug resistance will help us develop better strategies to regulate them efficiently and will finally pave the way toward better translation of miRNAs into clinics, developing them into a promising approach in cancer therapy.

/pdf/the-role-and-mechanisms-of-action-of-micrornas-in-cancer-3reepz2l36.pdf

The role and mechanisms of action of microRNAs in cancer drug resistance.

Every year more than 13 million deaths worldwide are due to environmental pollutants, and approximately 24% of diseases are caused by environmental exposures that might be averted through preventive measures. Rapidly growing evidence has linked environmental pollutants with epigenetic variations, including changes in DNA methylation, histone modifications and microRNAs.

Environ mental chemicals and epigenetic changes All of these mechanisms are likely to play important roles in disease aetiology, and their modifications due to environmental pollutants might provide further understanding of disease aetiology, as well as biomarkers reflecting exposures to environmental pollutants and/or predicting the risk of future disease. We summarize the findings on epigenetic alterations related to environmental chemical exposures, and propose mechanisms of action by means of which the exposures may cause such epigenetic changes. We discuss opportunities, challenges and future directions for future epidemiology research in environmental epigenomics. Future investigations are needed to solve methodological and practical challenges, including uncertainties about stability over time of epigenomic changes induced by the environment, tissue specificity of epigenetic alterations, validation of laboratory methods, and adaptation of bioinformatic and biostatistical methods to high-throughput epigenomics. In addition, there are numerous reports of epigenetic modifications arising following exposure to environmental toxicants, but most have not been directly linked to disease endpoints. To complete our discussion, we also briefly summarize the diseases that have been linked to environmental chemicals-related epigenetic changes.

https://www.mtpinnacle.com/pdfs/Environmental-chemical-exposures-and-human-epigenetics.pdf

Environmental chemical exposures and human epigenetics

Snail1 is the founding member of the Snail superfamily of zinc-finger transcription factors, which also includes Snail2 (Slug) and Snail3 (Smuc). The superfamily is involved in cell differentiation and survival, two processes central in cancer research. Encoded by the SNAI1 gene located on human chromosome 20q13.2, Snail1 is composed of 264 amino acids and usually acts as a transcriptional repressor. Phosphorylation and nuclear localization of Snail1, governed by PI3K and Wnt signaling pathways crosstalk, are critical in Snail1’s regulation. Snail1 has a pivotal role in the regulation of epithelial-mesenchymal transition (EMT), the process by which epithelial cells acquire a migratory, mesenchymal phenotype, as a result of its repression of E-cadherin. Snail1-induced EMT involves the loss of E-cadherin and claudins with concomitant upregulation of vimentin and fibronectin, among other biomarkers. While essential to normal developmental processes such as gastrulation, EMT is associated with metastasis, the cancer stem cell phenotype, and the regulation of chemo and immune resistance in cancer. Snail1 expression is a common sign of poor prognosis in metastatic cancer, and tumors with elevated Snail1 expression are disproportionately difficult to eradicate by current therapeutic treatments. The significance of Snail1 as a prognostic indicator, its involvement in the regulation of EMT and metastasis, and its roles in both drug and immune resistance point out that Snail1 is an attractive target for tumor growth inhibition and a target for sensitization to cytotoxic drugs.

/pdf/central-role-of-snail1-in-the-regulation-of-emt-and-57qyk95mz5.pdf

Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention

Methylation of multiple genes as a candidate biomarker in non-small cell lung cancer.

BACKGROUND:

MicroRNAs (miRNAs) have been identified as important posttranscriptional regulators involved in various biological and pathological processes of cells, but their association with tumor chemoresistance has not been fully understood.



METHODS:

We detected miRNA-200b (miR-200b) expression in different lung adenocarcinoma cell lines and then focused on its roles in regulation of docetaxel chemoresistance. We also identified E2F3 as a novel target of miR-200b.



RESULTS:

Based on miRNA microarray data, miR-200b was identified as the most down-regulated miRNA in docetaxel-resistant SPC-A1/DTX cells compared with parental SPC-A1 cells. Ectopic miR-200b expression reversed docetaxel chemoresistance of lung adenocarcinoma cells through cell proliferation inhibition, apoptosis enhancement, and G2/M cell cycle arrest. In a nude mouse xenograft model, up-regulation of miR-200b significantly enhanced response of SPC-A1/DTX cells to docetaxel. Luciferase reporters containing the 3′ untranslated region sequence of E2F3 messenger RNA were used to demonstrate that miR-200b could directly target E2F3. Small interfering RNA–mediated E2F3 knockdown revealed similar effects as that of ectopic miR-200b expression. Decreased miR-200b expression was also detected in tumor tissues sampled from lung adenocarcinoma patients treated with docetaxel-based chemotherapy and was proved to be correlated with high expression of E2F3, decreased sensitivity to docetaxel, and poor prognosis.



CONCLUSIONS:

Our results suggest that down-regulation of miR-200b could lead to E2F3 overexpression and in turn contribute to chemoresistance of lung adenocarcinoma cells to docetaxel. Cancer 2011. © 2011 American Cancer Society.

MicroRNA-200b Reverses Chemoresistance of Docetaxel-Resistant Human Lung Adenocarcinoma Cells by Targeting E2F3

MiR-100 resensitizes docetaxel-resistant human lung adenocarcinoma cells (SPC-A1) to docetaxel by targeting Plk1

The role of Kallikrein 10 gene (KLK10) in non-small cell lung cancer (NSCLC) remains largely unknown. We determined the frequency and functional significance of KLK10 hypermethylation in NSCLC. The mRNA expression and methylation status of KLK10 in 78 pairs NSCLC specimens was explored. The biological effects of KLK10 were analyzed by transfection. The results showed that, KLK10 was significantly downregulated in NSCLC (57.7%, 45/78) as compared to non-cancer samples (P = 0.010). CpG island hypermethylation of KLK10 was detected in 46.2% (36/78) NSCLC tissues and was closely correlated with loss of transcript (P < 0.001). KLK10 methylation was associated with advanced stage (P = 0.013) and lymph metastasis (P = 0.015). Furthermore, demethylation treatment restored the expression of KLK10 in two lung adencarcinoma cell lines (A549, SPC-A1). Forced expression of KLK10 in A549 and SPC-A1 remarkably suppressed cells proliferation, migration in vitro and oncogenicity in vivo. Additionally, methylated KLK10 was detected in 38.7% (30/78) of plasma samples from cancer patients but rare in cancer-free controls (P < 0.001). In conclusion, KLK10 acts as a functional tumor suppressor gene in NSCLC, epigenetic inactivation of KLK10 is a common event contributing to NSCLC pathogenesis and may be used as a potential biomarker.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1349-7006.2009.01486.x

Frequent transcriptional inactivation of Kallikrein 10 gene by CpG island hypermethylation in non-small cell lung cancer

Background
Regulator of G-protein signaling 5 (RGS5), a tissue-specific signal regulating molecular, plays important roles in the development of vasculature. Recently, we have found that the mRNA level of RGS5 was oppositely related with tumor metastasis in non-small cell lung cancer (NSCLC). However, the distribution of RGS5 in NSCLC and its significance need further study. We therefore investigated the expression of RGS5 in NSCLC, as well as its relationship with clinicopathologic parameters.

Methods
Tumor tissues from 51 NSCLC patients were analyzed and expression of RGS5 in tumor tissues was examined by immunohistochemistry. Chi-square test (or Fisher's exact test), Breslow test and multivariate Cox regression model were performed for statistical analysis.

Results
RGS5 were highly expressed in 47% (24/51) of NSCLC specimens. Expression of RGS5 was associated with tumor cell differentiation in NSCLC and low expression of RGS5 was strongly associated with cancer vasculature invasion and lymph node metastasis in NSCLC. Patients with high RGS5 expression in NSCLC had a prolonged progression free survival (15.0 months (95%CI: 6.1–23.9) vs. 6.0 months (95%CI: 1.3–10.7), P = 0.030).

Conclusion
RGS5 might be involved in cancer differentiation and metastasis in NSCLC. And it might be a candidate prognostic marker for PFS in NSCLC. J. Surg. Oncol. 2012;105:420–424. © 2011 Wiley Periodicals, Inc.

The relationship between RGS5 expression and cancer differentiation and metastasis in non‐small cell lung cancer

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