Reduced symmetric dimethylation stabilizes vimentin and promotes metastasis in MTAP-deficient lung cancer.

The aggressive nature and poor prognosis of lung cancer led us to explore the mechanisms driving disease progression. Utilizing our invasive cell-based model, we identified methylthioadenosine phosphorylase (MTAP) and confirmed its suppressive effects on tumorigenesis and metastasis. Patients with low MTAP expression display worse overall and progression-free survival. Mechanistically, accumulation of methylthioadenosine substrate in MTAP-deficient cells reduce the level of protein arginine methyltransferase 5 (PRMT5)-mediated symmetric dimethylarginine (sDMA) modification on proteins. We identify vimentin as a dimethyl-protein whose dimethylation levels drop in response to MTAP deficiency. The sDMA modification on vimentin reduces its protein abundance but trivially affects its filamentous structure. In MTAP-deficient cells, lower sDMA modification prevents ubiquitination-mediated vimentin degradation, thereby stabilizing vimentin and contributing to cell invasion. MTAP and PRMT5 negatively correlate with vimentin in lung cancer samples. Taken together, we propose a mechanism for metastasis involving vimentin post-translational regulation.

Efficacy of a multicomponent exercise training program intervention in community-dwelling older adults during the COVID-19 pandemic: A cluster randomized controlled trial.

The coronavirus disease 2019 (COVID-19) pandemic caused changes in lifestyle for older adults such as reduced physical activity and community participation. Community activity centers were randomly assigned to the intervention (n = 82) or control arm (n = 85). The intervention comprised one 60 min group exercise session per week in weeks 1-8 and an online home exercise program in weeks 9-16. Physical activity, physical performance, and prefrailty rates were assessed at baseline and 16 weeks. At 16 weeks, compared to the control arm, the intervention arm exhibited improved (p < 0.05) leisure-time physical activity (phi = 0.571), vigorous physical activity (phi = 0.534), and moderate-vigorous physical activity (phi = 0.344); prefrailty rates (phi = 0.179); and short physical performance battery results (η2p = 0.113). The intervention thus effectively improved physical activity levels, physical performance, and prefrailty rates in community-dwelling older adults during the COVID-19 pandemic.

Examining the links between regular leisure-time physical activity, sitting time and prefrailty in community-dwelling older adults.

AIMS: To examine the relationship between leisure-time physical activity, sitting time and prefrailty in community-dwelling older adults. DESIGN: Cross-sectional study. METHODS: Between February and July 2019, 539 individuals over age 60 were recruited in northern Taiwan. Demographic, medical history, physical activity and frailty data were analysed using descriptive statistics, chi-square tests and logistic regression. RESULTS: The prevalence of prefrailty was 24.4%; 33.2% had regular leisure-time physical activity, and 14.7% reported >6 hrs daily sitting time. Compared with individuals having regular leisure-time physical activity and shorter sitting times (daily average ≤6 hrs), those having no regular leisure-time physical activity and also shorter sitting times (adjusted OR, 1.80; 95% CI, 1.12, 2.92), or those also having regular leisure-time physical activity but longer sitting times (adjusted OR, 4.42; 95% CI, 2.22, 8.79) had an increased prefrailty risk. CONCLUSIONS: Having no regular leisure-time physical activity or longer sitting times is associated with a higher risk of prefrailty. For sedentary older adults to prevent prefrailty, they can become more active, sit less or better yet, commit to both.

MicroRNA signature predicts survival and relapse in lung cancer.

We investigated whether microRNA expression profiles can predict clinical outcome of NSCLC patients. Using real-time RT-PCR, we obtained microRNA expressions in 112 NSCLC patients, which were divided into the training and testing sets. Using Cox regression and risk-score analysis, we identified a five-microRNA signature for the prediction of treatment outcome of NSCLC in the training set. This microRNA signature was validated by the testing set and an independent cohort. Patients with high-risk scores in their microRNA signatures had poor overall and disease-free survivals compared to the low-risk-score patients. This microRNA signature is an independent predictor of the cancer relapse and survival of NSCLC patients.

Flexibility of internal and external glenohumeral rotation of junior female tennis players and its correlation with performance ranking.

[Purpose] The purpose of this study was to compare the internal and external rotation of the dominant and nondominant shoulders of adolescent female tennis players. The correlation between the shoulder rotation range of motion and the player's ranking was also analyzed. [Subjects and Methods] Twenty-one female junior tennis players who were 13 to 18 years old participated in this study. A standard goniometer was used to measure the internal and external rotation of both glenohumeral joints. The difference in internal and external rotation was calculated as the glenohumeral rotation deficit. The year-end ranking of each player was obtained from the Chinese Taipei Tennis Association. [Results] The internal rotation of the dominant shoulder was significantly smaller than that of the nondominant shoulder. Moreover, player ranking was significantly and negatively correlated with the internal rotation range of motion of both shoulders. On the other hand, the correlations of the internal and external rotation ranges of motion with the age, height, and weight were not significant. [Conclusion] The flexibility of the glenohumeral internal rotation is smaller in the dominant shoulder than of the nondominant shoulder in these junior female tennis players. Flexibility of the glenohumeral internal rotation may be a factor affecting performance in junior female tennis players.

MITF functions as a tumor suppressor in non-small cell lung cancer beyond the canonically oncogenic role.

Microphthalamia-associated transcription factor (MITF) is a critical mediator in melanocyte differentiation and exerts oncogenic functions in melanoma progression. However, the role of MITF in non-small cell lung cancer (NSCLC) is still unknown. We found that MITF is dominantly expressed in the low-invasive CL1-0 lung adenocarcinoma cells and paired adjacent normal lung tissues. MITF expression is significantly associated with better overall survival and disease-free survival in NSCLC and serves as an independent prognostic marker. Silencing MITF promotes tumor cell migration, invasion and colony formation in lung adenocarcinoma cells. In xenograft mouse model, MITF knockdown enhances metastasis and tumorigenesis, but decreases angiogenesis in the Matrigel plug assay. Whole transcriptome profiling of the landscape of MITF regulation in lung adenocarcinoma indicates that MITF is involved in cell development, cell cycle, inflammation and WNT signaling pathways. Chromatin immunoprecipitation assays revealed that MITF targets the promoters of FZD7, PTGR1 and ANXA1. Moreover, silencing FZD7 reduces the invasiveness that is promoted by silencing MITF. Strikingly, MITF has significantly inverse correlations with the expression of its downstream genes in lung adenocarcinoma. In summary, we demonstrate the suppressive role of MITF in lung cancer progression, which is opposite to the canonical oncogenic function of MITF in melanoma.

FAM198B Is Associated with Prolonged Survival and Inhibits Metastasis in Lung Adenocarcinoma via Blockage of ERK-Mediated MMP-1 Expression.

Purpose: The comprehensive understanding of mechanisms involved in the tumor metastasis is urgently needed for discovering novel metastasis-related genes for developing effective diagnoses and treatments for lung cancer.Experimental Design: FAM198B was identified from an isogenic lung cancer metastasis cell model by microarray analysis. To investigate the clinical relevance of FAM198B, the FAM198B expression of 95 Taiwan lung adenocarcinoma patients was analyzed by quantitative real-time PCR and correlated to patients' survivals. The impact of FAM198B on cell invasion, metastasis, and tumor growth was examined by in vitro cellular assays and in vivo mouse models. In addition, the N-glycosylation-defective FAM198B mutants generated by site-directed mutagenesis were used to study protein stability and subcellular localization of FAM198B. Finally, the microarray and pathway analyses were used to elucidate the underlying mechanisms of FAM198B-mediated tumor suppression.Results: We found that the high expression of FAM198B was associated with favorable survival in Taiwan lung adenocarcinoma patients and in a lung cancer public database. Enforced expression of FAM198B inhibited cell invasion, migration, mobility, proliferation, and anchorage-independent growth, and FAM198B silencing exhibited opposite activities in vitro FAM198B also attenuated tumor growth and metastasis in vivo We further identified MMP-1 as a critical downstream target of FAM198B. The FAM198B-mediated MMP-1 downregulation was via inhibition of the phosphorylation of ERK. Interestingly deglycosylation nearly eliminated the metastasis suppression activity of FAM198B due to a decrease of protein stability.Conclusions: Our results implicate FAM198B as a potential tumor suppressor and to be a prognostic marker in lung adenocarcinoma. Clin Cancer Res; 24(4); 916-26. ©2017 AACR.

HOXA5 inhibits metastasis via regulating cytoskeletal remodelling and associates with prolonged survival in non-small-cell lung carcinoma.

Homeobox genes comprise a family of regulatory genes that contain a common homeobox domain and act as transcription factors. Recent studies indicate that homeobox A5 (HOXA5) may serve as a tumour suppressor gene in breast cancers. However, the precise role and the underlying mechanism of HOXA5 in lung cancer remain unclear. Oligonucleotide microarrays and an invasion/metastasis lung adenocarcinoma cell line model were used to determine the correlation between HOXA5 expression and cancer cell invasion ability. We found that ectopic expression of HOXA5 in highly invasive cancer cells suppressed cell migration, invasion, and filopodia formation in vitro and inhibited metastatic potential in vivo. Knockdown of HOXA5 promoted the invasiveness of lung cancer cells. In addition, HOXA5 expression was associated with better clinical outcome in non-small cell lung cancer patients with wild-type EGFR. Furthermore, genome-wide transcriptomic and pathway analyses were performed to identify the potential molecular mechanisms. Our data showed that HOXA5 may bind to the promoters of the cytoskeleton-related genes and downregulate their mRNA and protein expression levels. Our studies provide new insights into how HOXA5 may contribute to the suppression of metastasis in lung cancer via cytoskeleton remodelling regulation. Therefore, targeted induction of HOXA5 may represent a promising approach for non-small-cell lung cancer therapy.