Association between low lung function and the increased risk of age-related macular degeneration: A population-based prospective cohort study.

Background: Low lung function is associated with an increased risk of age-related diseases. However, the relationship between age-related macular degeneration (AMD), the leading cause of blindness, and lung function remains unclear. We aimed to investigate whether low lung function increases the risk of AMD and the potential mechanisms behind this association. Methods: We conducted a prospective cohort analysis of 409 230 UK Biobank participants with completed lung function after excluding individuals with AMD. We used Cox proportional hazards models to estimate the risk of AMD incidence and mediation models to explore potential mechanisms driven by inflammatory markers, erythrocyte-related measures, and metabolites. Results: Overall, 6477 AMD cases were diagnosed across an average of 12.4 years of follow-up. Participants with low lung function had an increased risk of developing AMD compared to those with high lung function (forced vital capacity: adjusted hazard ratio (aHR) = 1.20 (95% confidence interval (CI) = 1.07-1.34); forced expiratory volume in one second: aHR = 1.32 (95% CI = 1.18-1.47); peak expiratory flow: aHR = 1.32 (95% CI = 1.20-1.45)). Inflammatory markers and erythrocyte-related measures mediated this relationship, acting as a pathway through which low lung function influenced AMD. The interactions of body mass index (BMI), sex, and smoking were significant and the effect of lung function on AMD was higher in men, obese, and smoking populations. Conclusions: The increased risk of AMD was associated with low lung function, with inflammatory and erythrocyte-related markers mediating this relationship. This suggests that improvements in lung function could reduce the risk of AMD, thereby promoting health and longevity.

circCDK13-loaded small extracellular vesicles accelerate healing in preclinical diabetic wound models.

Chronic wounds are a major complication in patients with diabetes. Here, we identify a therapeutic circRNA and load it into small extracellular vesicles (sEVs) to treat diabetic wounds in preclinical models. We show that circCDK13 can stimulate the proliferation and migration of human dermal fibroblasts and human epidermal keratinocytes by interacting with insulin-like growth factor 2 mRNA binding protein 3 in an N6-Methyladenosine-dependent manner to enhance CD44 and c-MYC expression. We engineered sEVs that overexpress circCDK13 and show that local subcutaneous injection into male db/db diabetic mouse wounds and wounds of streptozotocin-induced type I male diabetic rats could accelerate wound healing and skin appendage regeneration. Our study demonstrates that the delivery of circCDK13 in sEVs may present an option for diabetic wound treatment.

Association of exposure to ultraviolet radiation and warm-season ozone air pollution with incident age-related macular degeneration: A nationwide cohort study in China.

BACKGROUND: As the leading cause of blindness, age-related macular degeneration (AMD) performs an adverse impact on human health and disability. AMD have been reported to be associated with environmental factors; however, the association between ultraviolet (UV) radiation, warm-season ambient ozone pollution, and incident AMD remains unclear. METHODS: In this study, 19,707 participants without AMD at baseline were included from a nationwide longitudinal cohort in China. UV radiation and warm-season ozone exposure were evaluated through satellite-based models. Incident AMD was diagnosed via ophthalmological fundus images. Cox proportional hazard regression models were employed to explore the association of UV radiation and warm-season ozone with incident AMD, and the hazard ratios (HRs) and 95 % confidence intervals (CIs) were reported. RESULTS: During 312,935 person-month of follow-up, 3774 participants developed to AMD. High exposure to both UV radiation and warm-season ozone was associated with increasing risk of incident AMD, with HRs and 95 % CIs of 1.32 (1.23, 1.41) and 1.20 (1.11, 1.29) in two-exposure models, respectively. Moreover, negative interaction between UV radiation and warm-season ozone was identified, and it was found that exposure to high UV radiation and low ozone presented the highest hazard for AMD. Subgroup analyses showed that the UV-AMD association was stronger in southern China, while the ozone-AMD association was greater in northern China and rural areas. CONCLUSION: Our study provides the first epidemiological evidence that both UV radiation and warm-season ozone would elevate the risk of incident AMD, and the hazard of higher UV radiation may be attenuated by exposure to ozone. Strategies for decreasing AMD burden should jointly consider environmental exposures and geographic locations.

Associations between resting heart rate and cognitive decline in Chinese oldest old individuals: a longitudinal cohort study.

BACKGROUND: The trajectories of cognitive function in the oldest old individuals is unclear, and the relationship between resting heart rate (RHR) and cognitive decline is controversial. METHODS: 3300 participants who had cognitive function repeatedly measured 4 ~ 8 times were included, and latent class growth mixed models were used to identified the cognitive function trajectories. Cognitive decline was defined by the trajectory shapes, considering level and slope. After excluding individuals with sinus rhythm abnormal, 3109 subjects were remained and were divided into five groups by their RHR. Logistic regression models were used to estimate the relationship between RHR and cognitive decline. RESULTS: Three distinct cognitive function trajectory groups were identified: high-stable (n = 1226), medium-decreasing (n = 1526), and rapid-decreasing (n = 357). Individuals of medium/rapid-decreasing group were defined as cognitive decline. Adjusting for covariates, the odds ratios (95% confidence intervals) of RHR sub-groups were 1.19 (0.69, 2.05), 1.27 (1.03, 1.56), 1.30 (1.01, 1.67) and 1.62 (1.07, 2.47) for those RHR < 60 bpm, 70 ~ 79 bpm, 80 ~ 89 bpm and > 90 bpm respectively, compared with those RHR 60 ~ 69 bpm. The interaction effect between RHR and physical activity (PA) on cognitive decline was found, and stratification analysis was presented that higher RHR would only show risk effects on cognitive decline in those with physical inactivity (P < 0.05 for all). CONCLUSIONS: Our study demonstrates RHR more than 70 bpm present significant risk effect on cognitive decline, and this relationship is modified by PA. Elder population with physical inactivity and higher RHR should be paid more attention to prevent cognitive decline.

Trajectories of Blood Lipids Profile in Midlife Women: Does Menopause Matter?

Background It remains controversial whether changes of lipids over menopause transition (MT) are more age-related or more menopause-related. We aimed to classify women into different trajectory groups based on pattern and level of total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B (ApoB), high-density lipoprotein cholesterol (HDL-C), triglyceride, and apolipoprotein A-I over the MT, as well as examine the effect of MT-related factors on lipid trajectory groups and levels. Methods and Results The cohort included 2582 subjects from the Study of Women's Health Across the Nation. Different trajectory patterns of lipids during the MT were determined using the latent class growth mixture model. The predictors of distinct blood lipids trajectory groups were determined by multiple linear regression models and multinomial logistic regression models. Women were categorized into either inverse U-shape or progressing trajectory group in each blood lipids measurement. The inverse U-shape total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, high-density lipoprotein cholesterol, log(TG), and apolipoprotein A-I trajectories showed an increasing trend before menopause but a decreasing trend after menopause. The U-shape total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B trajectories started to rise 5 years before menopause. Age at menopause, follicle-stimulating hormone, vasomotor symptoms, and estradiol predicted the shape and level of the women's lipids over the MT. Conclusions Distinct lipid trajectories were identified during the MT, and the existence of at least 1 trajectory in each lipid parameters suggested a contribution of menopause. Our study highlights the need for earlier and continuous surveillance of lipids during the MT.

Identification of common genetic polymorphisms associated with down-regulated gonadotropin levels in an exome-wide association study.

OBJECTIVE: To investigate whether common genetic polymorphisms are associated with gonadotropin levels after down-regulation with daily gonadotropin-releasing hormone agonist and whether the polymorphisms of candidate variants influence the ovarian response to exogenous gonadotropins. DESIGN: Genetic association study. SETTING: University-affiliated in vitro fertilization center. PATIENTS: Subjects enrolled in an exploratory exome-wide association study (n = 862), a replication exome-wide association study (n = 86), and a classifier validation study (n = 148) were recruited from September 2016 to October 2018, September 2019 to September 2020, and January 2021 to December 2021, respectively. The included patients were aged ≤40 years and had a basal follicle-stimulating hormone (FSH) ≤12 IU/L. INTERVENTIONS: All participants received a luteal phase down-regulation long protocol. Genome DNA was extracted from the peripheral blood leukocytes. For the exploratory and replication cohorts, exome sequencing was conducted on a HiSeq 2500 sequencing platform. The multiplex polymerase chain reaction amplification technique and next-generation sequencing also were performed in the exploratory and replication cohorts. For the samples of the validation cohort, Sanger sequencing was performed. MAIN OUTCOME MEASURES: The primary endpoint was the gonadotropin levels after down-regulation, and the secondary endpoints were hormone levels and follicle diameters during stimulation, the total dose of FSH, duration of FSH stimulation, number of oocytes retrieved, and clinical pregnancy rate. RESULTS: In the exploratory cohort, we identified that FSHB rs6169 (P=2.71 × 10-24) and its single-nucleotide polymorphisms in high linkage disequilibrium were associated with the down-regulated FSH level. The same locus was confirmed in the replication cohort. Women carrying the C allele of FSHB rs6169 exhibited higher average estradiol level during stimulation (P=6.82 × 10-5), shorter duration of stimulation, and less amount of exogenous FSH (Pduration=0.0002; Pdose=0.0024). In the independent validation set, adding rs6169 genotypes into the prediction model for FSH level after down-regulation enhanced the area under the curve from 0.560 to 0.712 in a logistic regression model, and increased prediction accuracy by 41.05% when a support vector machine classifier was applied. CONCLUSION: The C allele of FSHB rs6169 is a susceptibility site for the relatively high level of FSH after down-regulation, which may be associated with increased ovarian FSH sensitivity.

Association between Body Mass Index and Diabetes Mellitus Are Mediated through Endogenous Serum Sex Hormones among Menopause Transition Women: A Longitudinal Cohort Study.

OBJECTIVE: To explore whether and to what extent endogenous sex hormones mediate the association between overweight and diabetes risk in menopausal transition women. METHODS: Premenopausal women were from the Study of Women's Health Across the Nation, with measurements of serum sex hormone including sex hormone binding globulin (SHBG), testosterone (T), estradiol (E2), follicle-stimulating hormone (FSH), and dehydroepiandrosterone sulfate (DHAS) in first postmenopausal follow-up. At the last postmenopausal follow-up, hyperglycemia status was confirmed. The partial least squares (PLS) regression method was used to extract hormonal signals associated with body mass index (BMI). Hyperglycemia was defined as individuals with prediabetes or diabetes; overweight was defined as BMI ≥ 25 kg/m2. Causal mediation analysis was used to examine the mediation effect on the association between perimenopause overweight and post-menopause hyperglycemia through PLS score and individual sex hormones. RESULTS: The longitudinal study included 1438 normal glucose women with a baseline mean age (SD) of 46.5 (2.6) years and a mean follow-up period of 9.9 years. During the follow-up period, 145 (10.1) cases of hyperglycemia occurred. Compared with normal-weight participants, overweight women were associated with a higher hyperglycemia risk during the transition period (OR = 4.06, 95% CI: 2.52 to 6.80). Overweight women had higher T, E2, and lower SHBG, FSH, and DAHS concentrations (ß = 0.26, 0.38, -0.52, -0.52, and -0.13, p < 0.05 for all). After adjusting for overweight and covariates, lower SHBG and FSH levels were associated with higher hyperglycemia risk (OR = 0.70 and 0.69, all p < 0.05). As a linear combination of sex hormones, the PLS score was positively associated with T, E2, and negatively with SHBG, FSH, and DHAS. PLS score interpreted 36.50% (p < 0.001) of the overweight-hyperglycemia association. Considering single-sex hormones, the mediation proportion of SHBG and FSH were 21.38% (p < 0.001) and 24.08% (p < 0.001). CONCLUSIONS: Sex hormones mediated the association of overweight and diabetes risk in menopause transition women. SHBG and FSH have the dominant mediation effect.

Baseline and longitudinal trajectories of body-mass index and all-cause mortality among patients with type 2 diabetes.

AIM: To investigate the associations of baseline body mass index (BMI) and longitudinal BMI trajectories with all-cause mortality among patients with type 2 diabetes mellitus (T2DM). METHODS,: We used data from the diabetes surveillance system of Yinzhou Health Information System with T2DM patients registered from 2010 to 2015. Participants aged ≥ 40 years were included and were followed up until September 30, 2021. The latent class growth mixture model was used to identify different changing patterns in BMI for 5 years from registration. Cox proportional hazards models were used to examine the associations of baseline BMI and 5-year BMI trajectories with all-cause mortality. RESULTS: We observed a nonlinear association between baseline BMI and all-cause mortality (P for nonlinearity < 0.001), with an increased risk of death for low but not high BMI. However, compared with participants with medium-stable BMI for 5 years from baseline, individuals with increasing BMI had higher mortality, with adjusted hazard ratios (95% confidence intervals) 1.21 (1.02;1.43) for early-increasing and 1.47 (1.19;1.80) for late-sharp increasing groups. CONCLUSION: These findings suggest that while obesity itself may not be associated with an increased risk for mortality, weight gain, and in particular rapid weight gain, is a risk factor for mortality among patients with T2DM.

Life-course blood pressure trajectories and incident diabetes: A longitudinal cohort in a Chinese population.

Background: Blood pressure levels are correlated with diabetes among middle-aged or older adults. However, longitudinal trajectories of blood pressure during young adulthood and their impact on diabetes have been insufficiently studied. Methods: The longitudinal cohort consisted of 4,625 adults who had blood pressure and body mass index (BMI) repeatedly measured five to nine times during 18-60 years of age. Distinct systolic blood pressure (SBP) trajectories were identified by a group-based trajectory model. Logistic regression analyses were used to investigate the association between trajectory patterns or quartiles of area under the curve values of SBP trajectories and incident diabetes, respectively. Results: Four distinct trajectory groups were identified for SBP: normotensive-stable (n = 761, 16.5%), prehypertension-stable (n = 2,381, 51.5%), stage I hypertension-increasing (n = 1,231, 26.6%), and stage II hypertension-increasing (n = 251, 5.4%). Compared with subjects who remained at SBP <120 mmHg in the normotensive-stable group, individuals in the prehypertension-stable trajectory exhibited a normal SBP range (<140 mmHg), and they still had a significantly higher risk of diabetes (adjusted OR = 1.82, p = 0.029). Individuals had a greater risk of diabetes in the stage I hypertension-increasing group (adjusted OR = 2.31, p = 0.006) and the highest risk in the stage II hypertension-increasing group (adjusted OR = 3.91, p < 0.001) relative to the normotensive-stable group. Furthermore, compared with the first quartile, adjusted ORs (95% CIs) of the fourth quartile of SBP incremental and total AUC were 2.50 (1.61-3.97) and 1.82 (1.15-2.94), respectively. Conclusions: Long-term SBP trajectory is a significant predictor for incident diabetes, which is independent of baseline SBP and body weight, attaching importance to maintaining optimal blood pressure levels and controlling changing slopes of SBP for preventing diabetes.

Joint trajectories of body mass index and waist circumference in early-life to mid-life adulthood and incident hypertension: the China Health and Nutrition Survey.

OBJECTIVE: This longitudinal study aims to identify distinct trajectories of body mass index (BMI) and waist circumference (WC) during 20-60 years old, and explore their joint effect on incident hypertension. DESIGN: A longitudinal cohort study. SETTING: China Health and Nutrition Survey, 1993-2011. PARTICIPANTS: The longitudinal cohort included 6571 participants (3063 men) who had BMI and WC repeatedly measured 3-7 times before incident hypertension or loss to follow-up. OUTCOMES: Hypertension was defined as systolic blood pressure/diastolic blood pressure>140/90 mm Hg or diagnosis by medical records or taking antihypertensive medication. RESULTS: Two distinct trajectories were characterised for both BMI and WC: low-increasing and high-increasing. Jointly, subjects were divided into four groups: normal (n=4963), WC-increasing (n=620), BMI-increasing (n=309) and BMI&WC-increasing (n=679). Compared with the normal group, the adjusted HRs and 95% CIs for hypertension were 1.43 (1.19 to 1.74), 1.51 (1.19 to 1.92) and 1.76 (1.45 to 2.14) for WC-increasing, BMI-increasing and BMI&WC-increasing groups, respectively. The model-estimated levels and slopes of BMI and WC were calculated at each age point in 1-year interval according to the model parameters and their first derivatives, respectively. The associations between model-estimated levels and hypertension increased with age, with adjusted ORs and 95% CIs ranging from 0.92 (0.86 to 0.98) to 1.57 (1.47 to 1.67) for BMI and 0.98 (0.92 to 1.05) to 1.44 (1.35 to 1.53) for WC. Conversely, the ORs (95% CIs) of level-adjusted linear slopes decreased with age, ranging from 1.47 (1.38 to 1.57) to 0.97 (0.92 to 1.03) for BMI and 1.36 (1.28 to 1.45) to 0.99 (0.93 to 1.06) for WC. CONCLUSIONS: Our study demonstrates that the joint trajectories of BMI and WC have significant effect on future hypertension risk, and the changing slopes of BMI and WC during young adulthood are independent risk factors. Both BMI and WC should be paid more attention to prevent hypertension, and young adulthood may be a crucial period for intervention.

Body mass index trajectory from childhood to puberty and high blood pressure: the China Health and Nutrition Survey.

OBJECTIVES: The prevalence of childhood hypertension is rising in parallel with the increasing prevalence of overweight and obesity in children. How growth trajectories from childhood to puberty relate to high blood pressure (HBP) is not well defined. We aimed to characterise potential body mass index (BMI) dynamic changing trajectories from childhood to puberty and investigate their association with HBP. DESIGN: A dynamic prospective cohort. SETTING: China Health and Nutrition Survey 1991-2015. PARTICIPANTS: There were 1907 participants (1027 men and 880 women) in this study. OUTCOMES: The primary outcome was HBP defined as systolic blood pressure (SBP)/diastolic blood pressure (DBP) exceeding the standards or diagnosis by medical records or taking antihypertensive medication. RESULTS: A model of cubic parameters with three groups was chosen, labelled as normal increasing group (85.16%, n=1624), high increasing group (9.81%, n=187) and resolving group (5.03%, n=96). Compared with the normal increasing group, the unadjusted HRs (95% CIs) for the resolving and high increasing groups were 0.91 (0.45 to 1.86) and 1.88 (1.26 to 2.81), respectively. After adjusting for baseline age, region, sex, baseline BMI z-score, baseline SBP and baseline DBP in model 3, the HRs (95% CIs) for the resolving and high increasing groups were 0.66 (0.30 to 1.45) and 1.56 (1.02 to 2.38). CONCLUSIONS: These results indicate that the BMI trajectories from childhood to puberty have significant impact on HBP risk. Puberty is a crucial period for the development of HBP.

Second primary malignancy among malignant solid tumor survivors aged 85 years and older.

The cancer burden in the oldest old has increased rapidly. This study aimed to investigate the epidemiology of second primary malignancy (SPM) in malignant solid tumor survivors aged 85 years and older utilizing the Surveillance, Epidemiology, and End Results (SEER) database. A total of 128,466 malignant solid tumor patients had been identified between 2000 and 2011, including 6774 patients who developed a SPM. The overall crude incidence of developing a SPM was 5.3%. Considering death as a competing event, the 3, 5, and 10-year cumulative incidence was 1.9%, 3.2%, and 5.4%, respectively. Relative younger age, male gender, surgery history, local stage and first primary malignancy (FPM) site located in the urinary system were related to higher cumulative incidence. A median time interval of 24.0 months was found between diagnosis of FPM and SPM. The most common SPM site was digestive system, whereas the least common was oral cavity and pharynx. The median overall survival (OS) was 49.0 months, and the median survival after SPM was 13.0 months. Relative older age, male gender and black race were associated with worse OS and survival after SPM, as well as higher hazard ratios of death. In conclusions, this study performed a comprehensive analysis of SPM among malignant solid tumor survivors aged 85 years and older. Additional studies are needed to characterize the specific cancer type of interest.

Evaluation of lung tumor motion in a large sample: Target-related and clinical factors influencing tumor motion based on four-dimensional CT.

BACKGROUND AND PURPOSE: We aimed to analyze the influence of target-related and clinical factors on lung tumor motion based on four-dimensional CT (4DCT), and clarify the motion based on subgroups in lung stereotactic body radiation therapy. MATERIALS AND METHODS: 4DCT image data of 267 tumors from 246 patients were analyzed. The coordinates in the left-right (LR), anterior-posterior (AP), and cranial-caudal (CC) directions of the center of mass (COM) of the gross tumor volumes in 10 phases of 4DCT were measured. The peak-to-peak COM displacement in the LR, AP, CC, and 3D directions was calculated. The influence of target-related and clinical factors on tumor motion was evaluated using multivariate analysis. RESULTS: The tumor segment location correlated with the tumor motion in each direction. Tumor size was predictive of tumor motion in the 3D (p = 0.023) and AP directions (p = 0.049). The tumor motion for metastatic tumors was smaller than that for primary tumors in the LR (p = 0.019) and AP directions (p = 0.008). The CC motion for pulmonary surgery recipients (3.8 ± 4.5 mm) was less than that for patients who had not undergone surgery (5.6 ± 5.4 mm), and no significant clinical factor was observed. BSA and BMI were positively correlated with the motion in the CC (p = 0.02) and LR directions (p = 0.002). CONCLUSION: The tumor segment location was a good predictor of tumor motion. A larger tumor tends to have a smaller motion. Patients with metastatic tumors or those who have undergone pulmonary surgery exhibited smaller and more unpredictable tumor motions, which required individual assessments. Thus, clinical factors can potentially predict tumor motion.

Evaluation of Lung Tumor Target Volume in a Large Sample: Target and Clinical Factors Influencing the Volume Derived From Four-Dimensional CT and Cone Beam CT.

BACKGROUND AND PURPOSE: This study aimed to systematically evaluate the influence of target-related and clinical factors on volume differences and the similarity of targets derived from four-dimensional computed tomography (4DCT) and cone beam computed tomography (CBCT) images in lung stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS: 4DCT and CBCT image data of 210 tumors from 195 patients were analyzed. The internal gross target volume (IGTV) derived from the maximum intensity projection (MIP) of 4DCT (IGTV-MIP) and the IGTV from CBCT (IGTV-CBCT) were compared with the reference IGTV from 10 phases of 4DCT (IGTV-10). The target size, tumor motion, and the similarity between IGTVs were measured. The influence of target-related and clinical factors on the adequacy of IGTVs derived from 4DCT MIP and CBCT images was evaluated. RESULTS: The mean tumor motion amplitude in the 3D direction was 6.5 ± 5 mm. The mean size ratio of IGTV-CBCT and IGTV-MIP compared to IGTV-10 in all patients was 0.71 ± 0.21 and 0.8 ± 0.14, respectively. Female sex, greater BSA, and larger target size were protective factors, while the Karnofsky Performance Status, body mass index, and motion were risk factors for the similarity between IGTV-MIP and IGTV-10. Older age and larger target size were protective factors, while adhesion to the heart, coexistence with cardiopathy, and tumor motion were risk factors for the similarity between IGTV-CBCT and IGTV-10. CONCLUSION: Clinical factors should be considered when using MIP images for defining ITV, and when using CBCT images for verifying treatment targets.

ZEB1 Promotes Oxaliplatin Resistance through the Induction of Epithelial - Mesenchymal Transition in Colon Cancer Cells.

Background: Oxaliplatin (OXA) chemotherapy is widely used in the clinical treatment of colon cancer. However, chemo-resistance is still a barrier to effective chemotherapy in cases of colon cancer. Accumulated evidence suggests that the epithelial mesenchymal transition (EMT) may be a critical factor in chemo-sensitivity. The present study investigated the effects of Zinc finger E-box binding homeobox 1 (ZEB1) on OXA-sensitivity in colon cancer cells. Method: ZEB1expression and its correlation with clinicopathological characteristics were analyzed using tumor tissue from an independent cohort consisting of 118 colon cancer (CC) patients who receiving OXA-based chemotherapy. ZEB1 modulation of OXA-sensitivity in colon cancer cells was investigated in a OXA-resistant subline of HCT116/OXA cells and the parental colon cancer cell line: HCT116. A CCK8 assay was carried out to determine OXA-sensitivity. qRT-PCR, Western blot, Scratch wound healing and transwell assays were used to determine EMT phenotype of colon cells. ZEB1 knockdown using small interfering RNA (siRNA) was used to determine the ZEB1 contribution to OXA-sensitivity in vitro and in vivo (in a nude mice xenograft model). Result: ZEB1 expression was significantly increased in colon tumor tissue, and was correlated with lymph node metastasis and the depth of invasion. Compared with the parental colon cancer cells (HCT116), HCT116/OXA cells exhibited an EMT phenotype characterized by up-regulated expression of ZEB1, Vimentin, MMP2 and MMP9, but down-regulated expression of E-cadherin. Transfection of Si-ZEB1 into HCT116/OXA cells significantly reversed the EMT phenotype and enhanced OXA-sensitivity in vitro and in vivo. Conclusion: HCT116/OXA cells acquired an EMT phenotype. ZEB1 knockdown effectively restored OXA-sensitivity by reversing EMT. ZEB1 is a potential therapeutic target for the prevention of OXA-resistance in colon cancer.

BMP4 promotes metastasis of hepatocellular carcinoma by an induction of epithelial-mesenchymal transition via upregulating ID2.

The role of bone morphogenetic protein 4 (BMP4), a crucial epithelial-mesenchymal transition (EMT) mediator, in the progression of hepatocellular carcinoma (HCC) patients heretofore has not been elucidated. The present study analyzed BMP4 expression in tumors and paired non-tumorous liver tissue and its correlation with clinicopathological characteristics from two independent cohorts consisting of 420 HCC patients. Functional analysis of BMP4 was performed in Bel-7402 and HCCLM3 HCC cells, and in a murine HCC model. The downstream targets of BMP4 in HCC were screened and confirmed. The results indicated that BMP4 expression was significantly increased in HCC tissue and highly metastatic HCC cells. BMP4 expression was correlated with vein invasion, overall survival and recurrence-free survival of HCC. BMP4 promoted HCC EMT and metastasis in vitro, and consistently in vivo. BMP4 knockdown blocked EMT and tumor metastasis in nude mice. ID2 was up-regulated by recombinant human BMP4, resulting in HCC EMT. Knockdown of ID2 blocked BMP4-induced EMT. In conclusion, BMP4 promotes invasion and metastasis of HCC by an induction of EMT via up-regulating ID2. BMP4 may be a valuable prognostic factor and potential therapeutic target for HCC therapy.

Nestin overexpression in hepatocellular carcinoma associates with epithelial-mesenchymal transition and chemoresistance.

BACKGROUND: Nestin expression has been reported to be associated with the prognosis of many solid tumors including human hepatocellular carcinoma (HCC). The present study aimed to identify the role, if any, of Nestin in the chemotherapeutic treatment of HCC. METHODS: We determined Nestin expression in nine HCC cell lines and 220 tissue samples of advanced HCC patients (retrospectively registered) treated with FOLFOX regimens. We examined the correlations between Nestin expression and clinicopatholgical variables and HCC prognosis. Also, we used in vitro and in vivo methods to determine the effects of Nestin expression on HCC cell invasion, migration and chemosensitivity. RESULTS: Nestin expression was significantly increased in HCC tissues and drug-resistant cell lines, and the presence of high levels of Nestin was associated with poor survival. We also showed that drug-resistance occurred in HCC cells with epithelial-mesenchymal transition (EMT), which in turn enhanced invasion ability. Nestin depletion reversed drug-resistance in the Bel-7402/5-FU and Bel-7402/ADM cell lines. Nestin knockdown enhanced chemotherapeutic efficacy in nude mice. Moreover, Nestin up-regulation in Bel-7402 was associated with the activation of Wnt/ß-catenin signaling. CONCLUSION: Our findings suggest that Nestin inhibitors may be useful for the chemotherapy of HCC.