MicroRNAs (miRNA) mediate distinct gene regulatory pathways triggered by epidermal growth factor receptor (EGFR) activation, which occurs commonly in lung cancers with poor prognosis. In this study, we report the discovery and mechanistic characterization of the miRNA miR-7 as an oncogenic "oncomiR" and its role as a key mediator of EGFR signaling in lung cancer cells. EGFR activation or ectopic expression of Ras as well as c-Myc stimulated miR-7 expression in an extracellular signal-regulated kinase (ERK)-dependent manner, suggesting that EGFR induces miR-7 expression through a Ras/ERK/Myc pathway. In support of this likelihood, c-Myc bound to the miR-7 promoter and enhanced its activity. Ectopic miR-7 promoted cell growth and tumor formation in lung cancer cells, significantly increasing the mortality of nude mice hosts, which were orthotopically implanted with lung cancers. Quantitative proteomic analysis revealed that miR-7 decreased levels of the Ets2 transcriptional repression factor ERF, the coding sequence of which was found to contain a miR-7 complementary sequence. Indeed, ectopic miR-7 inhibited production of ERF messages with a wild-type but not a silently mutated coding sequence, and ectopic miR-7 rescued growth arrest produced by wild-type but not mutated ERF. Together, these results identified that ERF is a direct target of miR-7 in lung cancer. Our findings suggest that miR-7 may act as an important modulator of EGFRmediated oncogenesis, with potential applications as a novel prognostic biomarker and therapeutic target in lung cancer. Cancer Res; 70(21); 8822-31. ©2010 AACR.

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The evidence linking arsenic in drinking water with increased urinary cancer risk comes from populations in relatively high exposure areas (>100 μg/L), whereas studies from lower exposure areas (<100 μg/L) reported inconsistent results. A previous study conducted in northeastern Taiwan, where residents were exposed to relatively lower concentrations, reported increased risk of urinary cancer in a dose-response way. Using the same cohort with longer follow-up, we conducted analysis to elucidate the relationship between ingested arsenic and urinary cancer in lower exposure groups and assessed the influence of duration, recency, and latency of drinking arsenic-containing well water. A total of 8,086 residents from northeastern Taiwan were followed for 12 years. Incident urinary cancer was ascertained through linkage with the national cancer registry. All analysis was done by Cox proportional hazards regression models. There were 45 incidences of urinary cancer and a monotonic increased risk of urinary cancer was found with increasing arsenic concentration (P < 0.001). For the highly exposed (>100 μg/L), the relative risks (RR) were >5-fold, whereas the risk was elevated but not significant for low exposure (<100 μg/L). Relative to the arsenic concentration <10 μg/L, those who drank well water with higher concentration from birth [RR, 3.69; 95% confidence interval (95% CI), 1.31-10.4], still drank at enrollment (RR, 3.50; 95% CI, 1.33-9.22), and drank for >50 years (RR, 4.12; 95% CI, 1.48-11.5) had a significantly increased risk of urinary cancer. When restricted to urothelial carcinoma, all risk estimates including concentration and characteristics of well water consumption were higher.

Tumor cells have long been observed to share several biological characteristics with normal stem/progenitor cells; however, the oncogenic mechanisms underlying the lung stem/progenitor cell signaling remain elusive. Here, we report that SOX2, a self-renewal factor in lung stem/progenitor cells, is highly expressed in a subclass of lung cancer cells, the proliferation, survival, and chemoresistance of which are dependent on SOX2 signaling. Overexpression of SOX2 promotes oncogenic phenotypes in lung cancer cells; knockdown of SOX2 attenuated cell proliferation. We observed that SOX2 increased the expression of epidermal growth factor receptor (EGFR), and EGFR activation further upregulated SOX2 levels, forming a positive feedback loop. SOX2 expression promoted chemoresistance, and silencing of SOX2 perturbed mitochondrial function, causing marked apoptosis and autophagy. SOX2 induced BCL2L1, the ectopic expression of which rescued the effects of SOX2 silencing on apoptosis, autophagy, and mitochondrial function. SOX2 promoted tumor formation, along with increased cell proliferation in a xenograft mouse model. SOX2 expression is associated with poor prognosis in lung cancer patients; moreover, SOX2, EGFR, and BCL2L1 expression levels were significantly correlated in lung tumors. Our findings support the emerging role of SOX2 in cell proliferation and survival by eliciting oncogenic EGFR and BCL2L1 signaling with potential applications as a prognosis marker and a therapeutic target in lung cancer. STEM CELLS

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BackgroundArsenic is a strong stimulus of heme oxygenase (HO)-1 expression in experimental studies in response to oxidative stress caused by a stimulus. A functional GT-repeat polymorphism in the HO-1 gene promoter was inversely correlated to the development of coronary artery disease in diabetics and development of restenosis following angioplasty in patients. The role of this potential vascular protective factor in carotid atherosclerosis remains unclear. We previously reported a graded association of arsenic exposure in drinking water with an increased risk of carotid atherosclerosis. In this study, we investigated the relationship between HO-1 genetic polymorphism and the risk of atherosclerosis related to arsenic.MethodsThree-hundred and sixty-seven participants with an indication of carotid atherosclerosis and an additional 420 participants without the indication, which served as the controls, from two arsenic exposure areas in Taiwan, a low arsenic-exposed Lanyang cohort and a high arsenic-exposed LMN cohort, were studied. Carotid atherosclerosis was evaluated using a duplex ultrasonographic assessment of the extracranial carotid arteries. Allelic variants of (GT)n repeats in the 5'-flanking region of the HO-1 gene were identified and grouped into a short (S) allele (< 27 repeats) and long (L) allele (≥ 27 repeats). The association of atherosclerosis and the HO-1 genetic variants was assessed by a logistic regression analysis, adjusted for cardiovascular risk factors.ResultsAnalysis results showed that arsenic's effect on carotid atherosclerosis differed between carriers of the class S allele (OR 1.39; 95% CI 0.86-2.25; p = 0.181) and non-carriers (OR 2.65; 95% CI 1.03-6.82; p = 0.044) in the high-exposure LMN cohort. At arsenic exposure levels exceeding 750 μg/L, difference in OR estimates between class S allele carriers and non-carriers was borderline significant (p = 0.051). In contrast, no such results were found in the low-exposure Lanyang cohort.ConclusionsThis exploratory study suggests that at a relatively high level of arsenic exposure, carriers of the short (GT)n allele (< 27 repeats) in the HO-1 gene promoter had a lower probability of developing carotid atherosclerosis than non-carriers of the allele after long-term arsenic exposure via ground water. The short (GT)n repeat in the HO-1 gene promoter may provide protective effects against carotid atherosclerosis in individuals with a high level of arsenic exposure.

There is increasing evidence showing the role of fatty acids and their derived lipid intermediates in the regulation of skeletal muscle mass synthesis and function. However, the role of omega-3 fatty acids remains unclear. Therefore, we conducted a meta-analysis to evaluate the potential effects of omega-3 fatty acids on sarcopenia-related performances among the elderly. Eligible literature and reports of randomized controlled trials were comprehensively searched from the PubMed, Cochrane Library, ClinicalTrials.gov, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases until July, 2018. A total of 10 articles were available for the meta-analysis. There were minor benefits for muscle mass gain (0.33 kg; 95% CI: 0.05, 0.62) and timed up and go performance (−0.30 s; 95% CI: −0.43, −0.17). Subgroup analyses regarding muscle mass and walk speed indicated that omega-3 fatty acid supplements at more than 2 g/day may contribute to muscle mass gain (0.67 kg; 95% CI: 0.16, 1.18) and improve walking speed, especially for those receiving more than 6 months of intervention (1.78 m/sec; 95% CI: 1.38, 2.17). Our findings provide some insight into the effects of omega-3 fatty acids on muscle mass, especially for those taking supplements at more than 2 g/day. We also observed that a long period of omega-3 fatty acids supplementation may improve walking speed.