The Hippo pathway is crucial in organ size control and tumorigenesis. Dysregulation of the Hippo/YAP axis is commonly observed in gastric cancer, while effective therapeutic targets for the Hippo/YAP axis are lacking. Identification of reliable drug targets and the underlying mechanisms that could inhibit the activity of the Hippo/YAP axis and gastric cancer progression is urgently needed.We used several gastric cancer cell lines and xenograft models and performed immunoblotting, qPCR, and in vivo studies to investigate the function of CXCR7 in gastric cancer progression.In our current study, we demonstrate that the membrane receptor CXCR7 (C-X-C chemokine receptor 7) is an important modulator of the Hippo/YAP axis. The activation of CXCR7 could stimulate gastric cancer cell progression through the Hippo/YAP axis in vitro and in vivo, while pharmaceutical inhibition of CXCR7 via ACT-1004-1239 could block tumorigenesis in gastric cancer. Molecular studies revealed that the activation of CXCR7 could dephosphorylate YAP and facilitate YAP nuclear accumulation and transcriptional activation in gastric cancer. CXCR7 functions via G-protein Gαq/11 and Rho GTPase to activate YAP activity. Interestingly, ChIP assays showed that YAP could bind to the promoter region of CXCR7 and facilitate its gene transcription, which indicates that CXCR7 is both the upstream signalling and downstream target of the Hippo/YAP axis in gastric cancer.In general, we identified a novel positive feedback loop between CXCR7 and the Hippo/YAP axis, and blockade of CXCR7 could be a plausible strategy for gastric cancer.
Abstract Background Disturbances in sleep have been associated with systemic inflammation and increased susceptibility to various chronic diseases. However, the specific mechanisms by which sleep influences plasma protein expression and contributes to the increased risk of inflammatory bowel disease (IBD) have not been fully elucidated. Methods We analysed data from 381,228 participants in the UK Biobank. Sleep was scored with chronotype, sleep duration, insomnia, and daytime sleepiness. Adjusted odds ratios (ORs) for prevalent IBD in unhealthy sleep patterns were estimated, as well as adjusted hazard ratios (HRs) for incident IBD by sleep patterns. A subset cohort of 40,392 participants was used for proteomic profiling, with differential expression analysis and weighted gene co-expression network analysis (WGCNA) conducted. A proteomic prognostic risk model was also established using the least absolute shrinkage and selection operator (LASSO)-Cox regression. Results Among the 381,228 participants in the clinical cohort, 100,622 (26.4%) had unhealthy sleep (sleep score 0-2) at baseline. Prevalent IBD was associated with increased odds of unhealthy sleep (OR = 1.250, 95% CI: 1.165-1.340, p < 0.001, Figure 1). Participants with unhealthy sleep had a higher risk of incident IBD (HR = 1.237, 95% CI: 1.136-1.348, p < 0.001). In the proteomic cohort, unhealthy sleep and IBD displayed 182 common differentially expressed proteins. Enrichment analysis revealed significant inflammatory pathways, including positive regulation of cytokine production and immune cell activation. WGCNA identified seven module eigengenes, with unhealthy sleep impacting IBD through cell activation and chemotaxis pathway and amino acid and organic acid metabolism. Incorporating protein biomarkers enhanced the performance of predicted models that achieved an AUC of 0.81 for predicting 2-year IBD onset. Unhealthy sleep participants with high protein scores were at high risk of incident IBD (HR=3.370, 95% CI: 2.300-4.938, p < 0.001), highlighting the importance of monitoring systemic inflammation. Conclusion Unhealthy sleep and IBD are bidirectionally linked, with inflammatory and metabolic proteins mediating the effect of poor sleep on IBD risk. Patients with sleep disturbances should be screened for inflammatory biomarkers to evaluate their IBD risk. Enhancing sleep quality may serve as an effective strategy for preventing and managing IBD. References Sleep disorders and inflammatory disease activity: chicken or the egg? Am J Gastroenterol. 2015 Apr;110(4):484-8.
To determine the survival rates of liver cancer in Qidong during the years 1972-2011, according to the data from a population-based cancer registry, in order to assess the long-term trends for prognosis of this cancer type.The deadline of the last follow-up for survival status of the 28, 398 registered cases was April of 2012. Cumulative observed survival (OS) and relative survival (RS) rates were calculated using Hakulinen's method performed by the SURV3.01 software developed by the Finnish Cancer Registry.The 1-, 3-, 5-, 10-and 15-year OS rates were 15.18%, 6.23%, 4.26%, 2.79% and 2.39%, respectively; the 1-, 3-, 5-, 10-and 15-year RS rates were 15.47%, 6.60%, 4.69%, 3.41% and 3.29%, respectively. For males, these OS rates were 14.95%, 6.05%, 4.06%, 2.67% and 2.26%, and these RS rates were 15.23%, 6.41%, 4.47%, 3.26% and 3.12%, respectively. For females, these OS rates were 15.89%, 6.79%, 4.87%, 3.17% and 2.80%, and these RS rates were 16.20%, 7.20%, 5.37%, 3.87% and 3.82%, respectively. No statistical differences were found between the male and female groups (P>0.05). The 5-year RS rates for age groups 15-34, 35-44, 45-54, 55-64, 65-74 and 75+ years-old were 4.42%, 4.29%, 4.96%, 4.67%, 4.67% and 6.35%, and the 10-year RS rates were 3.17%, 2.98%, 3.44%, 3.47%, 3.75% and 11.27%, respectively. Remarkable improvement was seen for the 1-, 3-, 5-, 10-and 15-year OS rates in this setting since the 1980s.The survival outcome from Qidong registered cases with liver cancer has shown gradual progress over the past four decades. Early detection and improvement of therapies may be responsible for the improved prognosis of liver cancer. While the disparity gap of survival between this area and developed countries is narrowing, there is still a need for improving the survival in Qidong.
Abstract Breast cancer is the most common malignancy for women worldwide, while Triple Negative Breast Cancer (TNBC) accounts for 20% in all patients. Compared with estrogen receptor positive breast cancer, which could be effectively controlled via endocrine therapy, TNBC is more aggressive and worse in prognosis. It is therefore urgent and necessary to develop a novel therapeutic strategy for TNBC treatment. Recent studies identified Hippo signaling is highly activated in TNBC, which could be a driving pathway for TNBC progression. In our study, we determine RNF187 as a negative regulator for Hippo signaling activation. RNF187 depletion significantly decreases cell migration and invasion capacity in TNBC. These effects could be rescued by further YAP depletion. Depletion of RNF187 increases the YAP protein level and Hippo signaling target genes, such as CTGF and CYR61 in TNBC. Immuno-precipitation assay shows that RNF187 associates with YAP, promoting its degradation possibly via inducing YAP K48-dependent poly-ubiquitination. Interestingly, Our clinical data reveals that RNF187 reversely correlates with YAP protein level and Hippo target genes. RNF187 tends to correlate with good prognosis in TNBC patients. Our study provides evidence to establish a proteolytic mechanism in regulation Hippo signaling activation in TNBC.
Abstract Background Long noncoding RNAs (lncRNA) represent significant factors of the mammalian transcriptome that mediates varied biological and pathological processes. The liver is the most common site for gallbladder cancer (GBC) distant metastasis and contributes to the majority of GBC‐related death. How lncRNA affects GBC metastasis is not completely understood. Results A novel lncRNA termed lncGALM (lncRNA in GBC associated with liver metastasis) was discovered to be highly expressed in cancer patients and xenografted tumors with liver metastasis. Elevated lncGALM in GBC patients also correlated to decreased survival. Invasion and migration of GBC cells were enhanced through lncGALM, both in vitro and in vivo. lncGALM functioned as sponges by competitively binding to and inactivating miR‐200 family members, which increase epithelial‐mesenchymal transition‐associated transcription factor ZEB1 and ZEB2, leading to a fibroblastic phenotype and increased expression of N‐cadherin. In addition, lncGALM bound to IL‐1β mRNA and stabilized the IL‐1β gene that mediates liver sinusoidal endothelial cell (LSECs) apoptosis. lncGALM‐expressing LiM2‐NOZ cells acquired a strong ability to migrate and adhere to LSECs, promoting LSECs apoptosis and therefore facilitating tumor cell extravasation and dissemination. Conclusions lncGALM promotes GBC liver metastasis by facilitating GBC cell migration, invasion, liver arrest, and extravasation via the invasion‐metastasis cascade. Targeting lncGALM may be protective against the development of liver metastasis in GBC patients.
A population-based cancer registry was established in Qidong, Jiangsu Province, China, in 1972, and the trends in incidence rates of the major cancer sites have been analyzed for a 25-year period, 1978-2002. Five-year age-specific rates, crude incidence rates, world age-standardized rates (ASR), percent change (PC) and annual percent change (APC) were calculated using annual data on population size, and estimates of its age structure. The indices of histological verification of diagnosis, death certificate only and proportion of mortality to incidence were employed for assessing the registration quality. A total of 51,933 incident cases of cancer were registered in Qidong from years 1978 to 2002, with a male-to-female sex ratio of 1.9:1. Crude incidence increased markedly over the 25-year period (PC and APC of +55.6% and +2.1%, respectively), but ASR showed a slight decrease (-0.4% in males, and -0.3% in females), indicating that the major part of this is due to population ageing. The leading cancer sites in rank were liver (average ASR = 50.8 per 100,000), stomach (26.7), lung (22.7), colon-rectum (8.9), oesophagus (7.4) and breast (5.4). Cancers of liver, lung, colon-rectum and female breast all showed increases in incidence during the study period, with APCs (ASR) of +0.1%, +1.7% and +1.4% for males, and +0.2%, +0.9%, +1.9% and +1.1% for females, while the cancers of stomach (APC: -3.2% in male, and --2.4% in female) and cervix (APC: -4.7%) showed notable declines. Examination of age-specific rates showed declining trends in the younger generations for liver cancer, but increases for cervix cancer. The results underline the increasing importance of cancer as a cause of mortality and morbidity in a population that is ageing and undergoing profound changes in socioeconomic development and lifestyle. The cancers of high lethality that have been common in the Chinese population (liver, stomach, oesophagus) are showing some evidence of decline, at least in younger generations, but they remain major problems. At the same time, the cancers associated with economically "developed" societies -- lung, colon-rectum and female breast -- are showing increases. The population-based cancer registry is an indispensable tool for providing data for planning and evaluation of programmes for cancer control in all societies.
Objective
The aim of this study was to set up a large, longitudinal and prospective database to investigate epidemiology, pathogenesis,the diagnosis, and prognosis of ankylosing spondylitis (AS) in Chinese population.
Methods
Four hundreds, and forty-nine consecutive outpatients with confirmed AS were recruited and followed annually. Characteristics of registration and demography (age, gender, time of back pain onset diagnosis, presence of AS-related clinical manifestations features, family history) and the current condition (disease activity, severity, treatment, laboratory tests) were collected at the clinic by rheumatologists. Dichotomous parameters were compared between groups using the χ2 test. Continuous parameters were compared using the analysis of variance.
Results
Four hundreds and forty-nine patients [(mean age: (29±8) years, male 84.0% (377/449), human leukocyte antigen (HLA)-B27 positive in 81.5% (309/379)] were included in the analysis. In this cross-sectional analysis only data at the first visit were used (from May 2014 to December2014). Differences in symptom duration (≤5 years, >5 years to ≤10 years and >10 years) were analyzed. The 3 groups did not differ in the frequency of gender, HLA-B27 positivity, family history, arthritis, enthesitis, inflammatory bowel disease, psoriasis, and abnormal C reactive protein (CRP). More patients with a higher prevalence of anterior chest wall [16.4%(27/165), 17.4%(26/149) vs 28.1%(38/135), χ2=7.477, P=0.024] and uveitis [5.5%(9/165), 8.9% (23/149) vs 18.5% (25/135), χ2=14.244, P<0.01].
Conclusion
This large cohort may improve our knowledge on the characteristics, pathogenesis and natural in chinese patienes with AS.
Key words:
Spondylitis, ankylosing; Prospective cohort; Symptom duration; Mobile health
Objective
To retrospectively analyze medical data of patients with colorectal cancer (CRC) so as to provide evidence for clinical use of opportunistic screening.
Methods
A total of 2450 CRC patients (male 1377, female 1073) who were treated at five hospitals in North China during October 2001 and September 2011 and had complete medical records and pathological results were recruited.The correlations of incidence of CRC with age, gender, tumor location and histological types were analyzed.
Results
Of all the CRC patients, those less than 50 years old accounted for 18.14%; and the incidence of CRC was substantially increased in those over 50 years old.Seventy-three percent of tumor occurred at the rectum and sigmoid colon, 6% at descending colon, 7% at transverse colon and 14% at ascending colon.Moderately, well or poorly differentiated adenocarcinoma accounted for 50.33%, 40.35% and 9.32%, respectively.Histological differentiation was not correlated with age and gender (P>0.05).
Conclusions
Age and gender should not be considered a determination of opportunistic screening for CRC.Colonoscopy is recommended as an alternative CRC screening procedure.
Key words:
Rectal neoplasm; Opportunistic screening; Colonoscopy; Clinical characteristics
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