BackgroundThe Dishevelled (Dvl) and Dishevelled-associated activator of morphogenesis 1 (Daam1) pathway triggered by Wnt5a regulates cellular polarity during development and tissue homoeostasis. However, Wnt5a signaling in breast cancer progression remains poorly defined.Methodology/Principal FindingsWe showed here that Wnt5a activated Dvl2, Daam1 and RhoA, and promoted migration of breast cancer cells, which was, however, abolished by Secreted Frizzled-related protein 2 (sFRP2) pretreatment. Dominant negative Dvl2 mutants or Dvl2 siRNA significantly decreased Wnt5a-induced Daam1/RhoA activation and cell migration. Ectopic expression of N-Daam1, a dominant negative mutant, or Daam1 siRNA remarkably inhibited Wnt5a-induced RhoA activation, stress fiber formation and cell migration. Ectopic expression of dominant negative RhoA (N19) or C3 exoenzyme transferase, a Rho inhibitor, decreased Wnt5a-induced stress fiber formation and cell migration.Conclusions/SignificanceTaken together, we demonstrated for the first time that Wnt5a promotes breast cancer cell migration via Dvl2/Daam1/RhoA.

The transition from non–muscle‐invasive bladder cancer (NMIBC) to muscle‐invasive bladder cancer (MIBC) is detrimental to bladder cancer (BLCA) patients. Here, we aimed to study the underlying mechanism of the subtype transition. Gene set variation analysis (GSVA) revealed the epithelial‐mesenchymal transition (EMT) signalling pathway with the most positive correlation in this transition. Then, we built a LASSO Cox regression model of an EMT‐related gene signature in BLCA. The patients with high risk scores had significantly worse overall survival (OS) and disease‐free survival (DFS) than those with low risk scores. The EMT‐related gene signature also performed favourably in the accuracy of prognosis and in the subtype survival analysis. Univariate and multivariate Cox regression analyses demonstrated that the EMT‐related gene signature, pathological N stage and age were independent prognostic factors for predicting survival in BLCA patients. Furthermore, the predictive nomogram model was able to effectively predict the outcome of BLCA patients by appropriately stratifying the risk score. In conclusion, we developed a novel EMT‐related gene signature that has tumour‐promoting effects, acts as a negative independent prognostic factor and might facilitate personalized counselling and treatment in BLCA.

microRNAs (miRNAs) have been proposed to be key regulators of diverse biological processes such as transcriptional regulation, cell growth and tumorigenesis. Wnt signaling plays an important role in the regulation of tumorigenesis and cancer progression. However, little is known about whether miR‐144 regulates bladder cancer cell proliferation by controlling Wnt signaling. In this study, we found that the miR‐144 expression level is significantly decreased in bladder cancer cell lines as well as in clinical cancer tissues. miR‐144 inhibitor blocks the expression of endogenous miR‐144 and promotes cancer cell proliferation, whereas miR‐144 overexpression is sufficient to inhibit cell proliferation. We further demonstrated that enhancer of zeste homolog 2 (EZH2) is a target gene of miR‐144. miR‐144 downregulation relieves miR‐144‐mediated repression of EZH2, which results in activation of Wnt/β‐catenin signaling and subsequent cell proliferation. These data suggest miR‐144 is an essential mediator of bladder cancer cell proliferation, thus offering a new target for the development of therapeutic agents against bladder cancer.

No abstract

The data on the prevalence of kidney stones in mainland China are still lacking. We performed the present meta-analysis to assess the stone prevalence in mainland China from 1990 through 2016. A total of 18 articles were included. The pooled overall prevalence was 7.54% (95% CI, 5.94–9.15). The prevalence in age groups of <20 years, 20–29 years, 30–39 years, 40–49 years, 50–59 years, and 60 years and older was 0.27%, 3.15%, 5.96%, 8.18%, 9.14%, and 9.68%, respectively, showing that it increased with age. Moreover, the prevalence was 10.34% in males and 6.62% in females, with an odds ratio (OR) of 1.63 [95% CI: 1.51–1.76], indicating that males are more likely to suffer from this disease than females. However, urban areas (6.03%, 95% CI: 3.39–8.68) and rural areas (7.48%, 95% CI: 3.39–11.57) did not differ in the stone prevalence rate (OR = 0.84, 95% CI: 0.42–1.68). The prevalence in the year groups of 1991–2000, 2001–2010, and 2011 to date was 5.95%, 8.86%, and 10.63%, respectively, which indicated an increasing trend. Further high-quality surveys throughout mainland China are needed to confirm these findings.

BCRL is a common complication for breast cancer patients after surgery. It can be fairly diagnosed only 1 month post-operation and the cumulative incidence of BCRL seems to be increasing over time, especially in the first year after surgery. ALND, radiotherapy, MRM, the number of positive axillary lymph nodes and BMI were found to be independent risk factors in the development of BCRL in this study.

BackgroundHypoxia-inducible factor 1 (HIF-1α) expression induced by hypoxia plays a critical role in promoting tumor angiogenesis and metastasis. However, the molecular mechanisms underlying the induction of HIF-1α in tumor cells remain unknown.Methodology/Principal FindingsIn this study, we reported that hypoxia could induce HIF-1α and VEGF expression accompanied by Rac1 activation in MCF-7 breast cancer cells. Blockade of Rac1 activation with ectopic expression of an inactive mutant form of Rac1 (T17N) or Rac1 siRNA downregulated hypoxia-induced HIF-1α and VEGF expression. Furthermore, Hypoxia increased PI3K and ERK signaling activity. Both PI3K inhibitor LY294002 and ERK inhibitor U0126 suppressed hypoxia-induced Rac1 activation as well as HIF-1α expression. Moreover, hypoxia treatment resulted in a remarkable production of reactive oxygen species (ROS). N-acetyl-L-cysteine, a scavenger of ROS, inhibited hypoxia-induced ROS generation, PI3K, ERK and Rac1 activation as well as HIF-1α expression.Conclusions/SignificanceTaken together, our study demonstrated that hypoxia-induced HIF-1α expression involves a cascade of signaling events including ROS generation, activation of PI3K and ERK signaling, and subsequent activation of Rac1.

The ATM (ataxia telangiectasia mutated) protein has recently been proposed to play critical roles in the response to mitochondrial dysfunction by initiating mitophagy. Here, we have used ATM-proficient GM00637 cells and ATM-deficient GM05849 cells to investigate the mitophagic effect of spermidine and to elucidate the role of ATM in spermdine-induced mitophagy. Our results indicate that spermidine induces mitophagy by eliciting mitochondrial depolarization, which triggers the formation of mitophagosomes and mitolysosomes, thereby promoting the accumulation of PINK1 and translocation of Parkin to damaged mitochondria, finally leading to the decreased mitochondrial mass in GM00637 cells. However, in GM05849 cells or GM00637 cells pretreated with the ATM kinase inhibitor KU55933, the expression of full-length PINK1 and the translocation of Parkin are blocked, and the colocalization of Parkin with either LC3 or PINK1 is disrupted. These results suggest that ATM drives the initiation of the mitophagic cascade. Our study demonstrates that spermidine induces mitophagy through ATM-dependent activation of the PINK1/Parkin pathway. These findings underscore the importance of a mitophagy regulatory network of ATM and PINK1/Parkin and elucidate a novel mechanism by which ATM influences spermidine-induced mitophagy.