Adipose tissue levels of polybrominated diphenyl ethers in relation to prognostic biomarkers and progression-free survival time of breast cancer patients in eastern area of southern China: A hospital-based study.

Evidence indicates that individual or groups of polybrominated diphenyl ethers (PBDEs) are associated with risk of breast cancer (BC). Epidemiological studies of PBDEs and BC progression are scarce. This study aimed to investigate the relationships between PBDE burdens in adipose tissues and prognostic biomarkers of BC as well as progression-free survival (PFS) of patients for the first time. The concentrations of 14 PBDE congeners in breast adipose tissues of 183 cases from the eastern area of southern China were analyzed by gas chromatography-mass spectrometry (GC-MS). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression models for the associations between PBDE levels and prognostic biomarkers. Kaplan-Meier and Cox regression analyses were conducted to identify the correlations between PBDEs and PFS. The results showed that BDE-99 and 190 levels were positively associated with clinical stage and N stage respectively (OR = 2.61 [1.26-5.40], OR = 2.78 [1.04-7.46]). Concentrations of BDE-28 and BDE-183 were negatively associated with the expression of estrogen receptor (ER) (OR = 0.30 [0.11-0.81]; 0.39 [0.15-0.99]) and progesterone receptor (PR) (OR = 0.36 [0.14-0.92]; 0.37 [0.15-0.91]), and increased BDE-47 was associated with lower human epidermal growth factor receptor 2 (HER2) expression (OR = 0.44 [0.23-0.86]). Adipose levels of BDE-71, 99, 138, 153, 154 and total PBDEs were positively associated with p53 expression (all P < 0.05). Finally, BDE-47, 99 and 183 were considered as independent prognostic factors for shorter PFS in the Cox models (adjusted hazard ratios = 3.14 [1.26-7.82]; 2.25 [1.03-4.94]; 2.60 [1.08-6.25], respectively). The recurrence risk and prognosis of BC may be closely bound to the body burdens of certain PBDE congeners. Further epidemiological and experimental studies are needed for confirmation.

Environmental Cadmium Exposure Promotes the Development, Progression and Chemoradioresistance of Esophageal Squamous Cell Carcinoma.

Cadmium (Cd) exposure has been implicated in the etiology of esophageal squamous cell carcinoma (ESCC), albeit with inconsistent results from epidemiologic studies and without causal evidence. In this study, we explore the relationship of Cd exposure and the development, progression and therapeutic resistance of ESCC. A total of 150 ESCC patients and 177 matched controls from a coastal region with a high incidence of ESCC in China were included in the study. It was found that the median blood Cd level (BCL) was significantly higher in ESCC patients than that in the controls. Odds ratios for ESCC risk were 3.12 (95% CI 1.54-6.30) and 3.71 (95% CI 1.84-7.48) in the third and fourth quartiles of Cd distribution, respectively. Notably, BCL above 4.71 µg/L was strongly associated with shorter progression-free survival time compared to that below 1.60 µg/L (p < 0.001). The chronic Cd-treated ESCC cells (CCT-ESCC) CCT-EC109 and CCT-EC9706 exhibited increased cell proliferation and tumorigenesis, enhanced migration and invasion, and upregulated EMT biomarkers following 12 weeks of exposure to 5 µM cadmium chloride. Furthermore, Cd treatment attenuated the efficacy of 5-fluorouracil, cisplatin and irradiation treatment in CCT-ESCC cells both in vitro and in vivo. Moreover, we revealed that Cd stimulated the cancer cell stemness and Wnt/ß-catenin signaling pathway in the CCT-ESCC cells. Additionally, 5-aza-2-deoxy-cytidine treatment resulted in suppression of the Wnt/ß-catenin signaling pathway and rescue of the Cd-induced cell radioresistance. These results offer new insights into the role of environmental Cd exposure in the development, progression and chemoradioresistance of ESCC.

Reducing N6AMT1-mediated 6mA DNA modification promotes breast tumor progression via transcriptional repressing cell cycle inhibitors.

DNA N6-methyladenosine (6mA) is a novel epigenetic signaling modification in humans and has been implicated in the progression and tumorigenesis of several cancers. However, the function and mechanism of 6mA in breast cancer (BC), the most common cancer among women, are unclear. Here, we found that decreases in N6AMT1 correlated with the extent of 6mA in clinical BC tissues and predicted a worse survival of BC patients. Functionally, knockdown of N6AMT1 markedly reduced 6mA in DNA and promoted colony formation and migration of BC cells, whereas overexpression of N6AMT1 had the opposite effect. Moreover, silencing of N6AMT1 reduced 6mA modification and enhanced the growth of BC cells in vitro and tumors in vivo. 6mA immunoprecipitation sequencing (6mA-IP-seq), RNA-seq, 6mA-IP-PCR, and bioinformatics analysis indicated that N6AMT1 was a functional methyltransferase for genomic 6mA DNA modifications and related to gene transcriptional activity. Critical negative regulators of the cell cycle, such as RB1, P21, REST, and TP53 were identified as targets of N6AMT1 in BC. These results suggest N6AMT1 enhances DNA 6mA levels to repress tumor progression via transcriptional regulation of cell cycle inhibitors.

Corrigendum: TRPC1 Inhibits Cell Proliferation/Invasion and Is Predictive of a Better Prognosis of Esophageal Squamous Cell Carcinoma.

[This corrects the article DOI: 10.3389/fonc.2021.627713.].

TRPC1 Inhibits Cell Proliferation/Invasion and Is Predictive of a Better Prognosis of Esophageal Squamous Cell Carcinoma.

BACKGROUND AND OBJECTIVES: In China, over 90% of esophageal cancer (EC) cases are esophageal squamous cell carcinoma (ESCC). ESCC is a frequently malignant tumor with poor prognosis despite the development of comprehensive therapeutic strategies, for which there is still a lack of effective prognostic factors. Previous studies found that the abnormal expression of TRPC1 is closely related to the proliferation, invasion, metastasis, and differentiation of various tumors. However, the relationship between TRPC1 and ESCC is currently unclear. The present study aimed to clarify the clinical significance of TRPC1 and to preliminarily assess the molecular mechanism by which TRPC1 regulates cell proliferation, migration, and invasion in ESCC. MATERIALS AND METHODS: Immunohistochemistry (IHC) was used to determine the expression of TRPC1 and Ki-67 in 165 cases of ESCC. The correlations between TRPC1 expression and clinicopathological characteristics were determined, and both univariate and multivariate analyses were utilized to quantify the impact of TRPC1 expression on patient survival. Cell Counting Kit-8, scratch wound healing, and transwell assays were used to determine the effects of TRPC1 on proliferation, migration, and invasion in ESCC in vitro, respectively. RESULTS: The positive expression rate of TRPC1 showed significantly decreased in ESCC (45.50%) compared with the levels in normal esophageal mucosa (NEM; 80.80%) and high-grade intraepithelial neoplasia (HGIEN; 63.20%) (P<0.001). Higher expression rate of TRPC1 was associated with low lymph node metastasis (P<0.001), high differentiation (rs = 0.232, P=0.003), and low Ki-67 (rs = -0.492, P<0.001). We further revealed that low expression of TRPC1 was associated with poor prognosis (Disease-free survival, DFS: 95% CI=0.545-0.845, P=0.001; Overall survival, OS: 95% CI=0.553-0.891, P=0.004). Furthermore, we showed that downregulation of TRPC1 promoted the proliferation, migration, and invasion of human esophageal squamous cell carcinoma cell line EC9706 in vitro. In contrast, overexpression of TRPC1 inhibited the proliferation, migration, and invasion of human esophageal squamous cell carcinoma cell line KYSE150 (P<0.01), in a manner at least in part mediated through the AKT/p27 pathway. CONCLUSION: TRPC1 inhibited the proliferation, migration, and invasion of EC9706 and KYSE150 cells, at least, in part mediated through the AKT/p27 pathway in vitro. The downregulation of TRPC1 may be one of the most important molecular events in the malignant progression of ESCC. TRPC1 could be a new candidate tumor suppressor gene and a new prognostic factor of ESCC.

Co-expression of VEGF-C and survivin predicts poor prognosis in esophageal squamous cell carcinoma.

BACKGROUND: Lymphatic metastasis is one of the main factors affecting prognosis in esophageal squamous cell carcinoma (ESCC). Vascular endothelial growth factor-C (VEGF-C) is an important factor that promotes lymphangiogenesis. Survivin also plays a significant role in lymphatic invasion. However, the role and mechanism of their co-expression are still unclear in ESCC. The purpose of this study was to investigate whether the co-expression of VEGF-C and survivin could be a potential marker to predict patient prognosis and survival in ESCC. METHODS: The levels of VEGF-C, vascular endothelial growth factor receptor 3 (VEGFR-3), survivin, and Ki-67 were determined by immunohistochemistry (IHC) in 97 ESCC patient tumors. The correlations of co-expression of VEGF-C and survivin with pathological features and survival results were also assessed. RESULTS: High VEGF-C expression was observed in 64.9% of the patients and significantly correlated with T stage (P=0.024), node status (P=0.038), and lymph node metastasis (P=0.015). High survivin expression was significantly associated with T stage (P=0.013), N stage (P=0.016), lymph node metastasis (P=0.005), and differentiation (P=0.044) in 67.0% of the patients. Co-expression of VEGF-C and survivin (V+S+) was significantly associated with T stage (P<0.001), N stage (P=0.015), lymph node metastasis (P=0.003), differentiation (P=0.0045), and Ki-67 levels (P=0.024). High expression of VEGF-C or survivin was associated significantly with worse disease-free survival (DFS) and overall survival (OS) (P<0.05). Moreover, the V+S+ group had a worse DFS (P<0.001) and OS (P=0.001) than any other group (i.e., V-S-, V+S-, V-S+). Furthermore, multivariate DFS analyses (95% CI: 1.147-2.220, P=0.006) and multivariate OS analyses (95% CI: 1.080-2.193, P=0.017) revealed that co-expression of VEGF-C and survivin was an independent prognostic factor in ESCC patients. CONCLUSIONS: Co-expression of VEGF-C and survivin was predictive of poor prognosis in ESCC. Combined detection of VEGF-C and survivin could represent a feasible and effective marker to predict the prognosis and survival of ESCC patients.

Chronic BDE-47 Exposure Aggravates Malignant Phenotypes and Chemoresistance by Activating ERK Through ERα and GPR30 in Endometrial Carcinoma.

Environmental exposure to certain compounds contribute to cell plasticity, tumor progression and even chemoresistance. 2,2',4,4'-tetrabromo diphenyl ether (BDE-47), one of the most frequently detected polybrominated diphenyl ethers (PBDEs) in environmental and biological samples, is a known estrogen disruptor closely associated with the development of hormone-dependent cancers. However, the effect of BDE-47 on endometrial carcinoma (EC), an estrogen-dependent cancer, remains to be elucidated. Mechanisms of estrogen receptor α (ERα) and G-protein-coupled receptor-30 (GPR30) involved in BDE-47 carcinogenesis are yet to be identified. This study aims to investigate the effect of BDE-47 on the invasive phenotype of estrogen-dependent EC cells. BDE-47-treated cells, such as Ishikawa-BDE-47 and HEC-1B-BDE-47 cells, exhibited increased cell viability and enhanced metastatic ability. In vivo studies showed larger tumor volumes and more metastasis in mice injected with Ishikawa-BDE-47 cells compared with parental Ishikawa cells. MTT assay showed that BDE-47 exposure could attenuate sensitivity of EC cells to cisplatin or paclitaxel treatment in vitro. Western blotting revealed overexpression of ERα, GPR30, pEGFR (phosphorylated epidermal growth factor receptor), and pERK (phosphorylated extracellular-regulated protein kinase) in Ishikawa-BDE-47 and HEC-1B-BDE-47 cells. Knockdown of ERα or GPR30 by small interfering RNA reversed the stimulating effect of BDE-47 on cell growth, migration and invasion of EC cells. Additionally, treatment with pEGFR or pERK inhibitor impaired cell viability, migration and invasion in Ishikawa-BDE-47 and HEC-1B-BDE-47 cells. Overall, our results indicate that chronic BDE-47 exposure triggers phenotypic plasticity, promotes progression and even chemoresistance in EC cells, at least in part, via ERα/GPR30 and EGFR/ERK signaling pathways.

Blood lead and cadmium levels associated with hematological and hepatic functions in patients from an e-waste-polluted area.

Chronic exposures to toxic trace metals have hazardous effects on human health, especially exposure to lead (Pb) and cadmium (Cd). Blood Pb and Cd reflect toxicity on human health. A total of 267 hospitalized patients, of which 158 were from Guiyu (exposed group) in China, and 109 from Jinping (reference group), were recruited in this study. Blood Pb and Cd were measured by graphite furnace atomic absorption spectrometry. Blood Pb and Cd levels from the exposed group were both higher than in the reference group. Blood Pb levels are positively associated with blood Cd levels from the two groups. Blood Pb and Cd levels are associated with elevated hematological and hepatic parameters in patients from the exposed and reference groups. The results suggest toxic trace metals may increase liver metabolic burden, inducing abnormal liver function.

Connecting gastrointestinal cancer risk to cadmium and lead exposure in the Chaoshan population of Southeast China.

Cadmium (Cd) and lead (Pb) pose a serious threat to human health because of its carcinogenicity. China ranks first according to the Global Cancer Report for 2014 in newly diagnosed gastrointestinal cancers and cancer deaths. The aim of the present study was to evaluate the association of Cd and Pb burden with the risk of gastrointestinal cancers in a hospital-based case-control study from southern regions of China, Chaoshan area. A total of 279 hospitalized patients were recruited in this study, of which 167 were gastrointestinal cancer cases (70 esophageal cancer, 51 gastric cancer, and 46 colorectal cancer), and 112 controls were recruited from two hospitals in the Chaoshan area of southeast China. Basic clinical data and information on gender, age, and other demographic characteristics were collected from medical records. Blood Cd and Pb levels were detected by graphite furnace atomizer absorption spectrophotometry (GFAAS). Blood Cd/Pb levels and over-limit ratios between cases and controls were compared by Mann-Whitney U and Kruskal-Wallis H tests. We used logistic regression to estimate odds ratios (ORs) as measures of relative risk and explored the relationships between blood Cd/Pb levels and gastrointestinal cancer risk and clinicopathological characteristics. Median levels of blood Cd and Pb in cases (2.12 and 60.03 µg/L, respectively) were significantly higher than those of controls (1.47 and 53.84 µg/L, respectively). The over-limit ratios for Cd (≥ 5 µg/L) and Pb (≥ 100 µg/L) in the cases were both higher than that of controls. Blood Cd levels had a tendency to accumulate in the human body with gender, age, and tobacco smoking, while blood Pb levels only were associated with tobacco smoking. The logistic regression model illustrated that gastrointestinal cancers were significantly associated with blood Cd levels and blood Pb levels. The concentrations of Cd and Pb in patients with T3 + T4 stage were markedly higher than in patients with T1 + T2. On the other hand, blood Cd levels were dramatically increased in the distant -metastasis (M1). Blood Cd and Pb levels are significantly higher in gastrointestinal cancers compared to controls. Cd and Pb appear to be risk factors for gastrointestinal cancers in Chaoshan region, and higher levels of Cd and Pb may promote the occurrence and progression of gastrointestinal cancers.

LIM and SH3 protein 1 promotes tumor proliferation and metastasis in lung carcinoma.

Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer-related mortality worldwide. In the present study, we focused on LIM and SH3 protein 1 (LASP-1), a key molecule involved in the development of multiple cancers, and attempted to elucidate its effect on the oncogenesis of lung cancer. We determined the expression level of LASP-1 in lung cancer using reverse transcription-quantitative polymerase chain reaction and western blot analysis, and also studied the potential function of LASP-1 in lung cancer cell growth, apoptosis and migration by small interfering RNA transfection. The results revealed that the levels of LASP-1 mRNA and protein were abnormally high in lung cancer cells. Following RNA interference of LASP-1, the proliferation and migration ability of the human cancer cell line A549 were significantly decreased. In addition, fluorescence-activated cell sorting analysis indicated that the apoptotic process in the A549 cell line was induced by the silencing of LASP-1. Our study is the first to investigate the potential of LASP-1 in lung cancer, and revealed its significant role in regulating the growth and metastasis of lung cancer cells. The present study suggests that LASP-1 has potential as a therapeutic target in the treatment of lung cancer in the clinic.

Cadmium exposure and the risk of breast cancer in Chaoshan population of southeast China.

Recently, there is increasing evidence indicating a link between cadmium exposure and human breast cancer. This study was aimed to explore the relationship between blood cadmium burden and the risk of breast cancer in Chaoshan women with no occupational exposure. Blood cadmium levels (BCLs) were determined in whole blood of 186 breast cancer cases and 139 controls. Basic clinical data and information of age, occupation, blood types, family cancer history, and disease history, as well as other demographic characteristics were collected from medical records. BCLs were detected by graphite-furnace atomizer absorption spectrophotometer (GFAAS). BCLs and proportions of BCLs over 3 µg/L between cases and controls were compared. The relationships between BCLs and breast cancer were explored by comparing BCL differences between/among different characteristics of investigated factors. In addition, BCLs within cases were also compared in relation to the disease clinical stages, tumor-node-metastasis (TNM) stages, and estrogen receptor (ER), progesterone receptor (PR), and Cerb-B2 expressions. The breast cancer patients had a higher median concentration of blood cadmium (2.28, interquartile range 1.57-3.15 µg/L) than the controls (1.77, 1.34-2.57 µg/L; P = 0.001). The proportion of BCLs over 3 µg/L was 2.35 times higher in the breast cancer cases than that of the controls after adjusting for age. Cadmium tends to accumulate in the human body with age and body mass index (BMI) but not associates with type of job, family history, disease history, and other investigated characters. With the increase of clinical stages and T and M stages, the BCLs in the breast cancer cases also increased. BCLs were positively associated with Cerb-B2 expression (r = 0.152, P = 0.038) but not significantly associated with ER and PR expressions. The data obtained show that cadmium concentration is significantly higher in blood of breast cancer patients in comparison to healthy controls. Cadmium seems to be a risk factor of breast cancer, and high cadmium exposure was observed in advanced stages of this disease, which indicates that it may promote the development of breast cancer.