Kang-Ai Injection Inhibits Gastric Cancer Cells Proliferation through IL-6/STAT3 Pathway.

OBJECTIVE: To explore the mechanisms underlying the proliferative inhibition of Chinese herbal medicine Kang-Ai injection (KAI) in gastric cancer cells. METHODS: Gastric cancer cell lines MGC803 and BGC823 were treated by 0, 0.3%, 1%, 3% and 10% KAI for 24, 48 and 72 h, respectively. The cell proliferation was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. The apoptosis and cell cycle were evaluated by flow cytometry. Interleukin (IL)-6 mRNA and protein expression levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immune sorbent assay (ELISA), respectively. The protein expression levels of cyclin A, cyclin E, cyclin B1, cyclin D1, p21, retinoblastoma (RB), protein kinase B (AKT), extracellular regulated protein kinases (ERK), signal transducer and activator of transcription (STAT) 1 and STAT3 were detected by Western blot. RESULTS: KAI inhibited the proliferation of MGC803 and BGC823 gastric cancer cells in dose- and time-dependent manner. After treated with KAI for 48 h, the proportion of G1 phase was increased, expression level of cyclin D1 and phosphorylation-RB were down-regulated, whereas the expression of p21 was up-regulated (all P<0.01). Furthermore, 48-h treatment with KAI decreased the phosphorylation level of STAT3, inhibited the mRNA and protein expressions of IL-6 (all P<0.01). IL-6 at dose of 10 ng/mL significantly attenuated the proliferative effect of both 3% and 10% KAI, and recovered KAI-inhibited STAT3 phosphorylation and cyclin D1 expression level (all P<0.01). CONCLUSION: KAI exerted an anti-proliferative function by inhibiting IL-6/STAT3 signaling pathway followed by the induction of G1 phase arrest in gastric cancer cells.

LncRNA APCDD1L-AS1 induces icotinib resistance by inhibition of EGFR autophagic degradation via the miR-1322/miR-1972/miR-324-3p-SIRT5 axis in lung adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor-tyrosinase kinase inhibitor (EGFR-TKI) resistance is the major obstacle in the treatment of lung adenocarcinoma (LUAD) patients harboring EGFR-sensitive mutations. However, the long non-coding RNAs (lncRNAs) related to EGFR-TKIs resistance and their functional mechanisms are still largely unknown. This study aimed to investigate the role and regulatory mechanism of lncRNA APCDD1L-AS1 in icotinib resistance of lung cancer. METHODS: Molecular approaches including qRT-PCR, MTT assay, colony formation, RNA interference and cell transfection, RNA immunoprecipitation (RIP), dual luciferase reporter assay, RNA fluorescence in situ hybridization, TUNEL assay, flow cytometry, immunoblotting, xenograft model and transcriptome sequencing were used to investigate the mechanism of APCDD1L-AS1 in icotinib resistance. RESULTS: A novel lncRNA, APCDD1L-AS1 was identified as the most significantly upregulated lncRNA in icotinib-resistant LUAD cells by the transcriptome sequencing and differential lncRNA expression analysis. We found that APCDD1L-AS1 not only promoted icotinib resistance, but also upregulated the protein expression level of EGFR. Mechanistically, APCDD1L-AS1 promoted icotinib resistance and EGFR upregulation by sponging with miR-1322/miR-1972/miR-324-3p to remove the transcription inhibition of SIRT5. Furthermore, SIRT5 elevated EGFR expression and activation by inhibiting the autophagic degradation of EGFR, finally promoting icotinib resistance. Consistently, the autophagy initiator rapamycin could decrease EGFR levels and increase the sensitivity of icotinib-resistant LUAD cells to icotinib. CONCLUSION: APCDD1L-AS1 could promote icotinib resistance by inhibiting autophagic degradation of EGFR via the miR-1322/miR-1972/miR-324-3p-SIRT5 axis. The combination of autophagy initiator and EGFR-TKIs might serve as a potential new strategy for overcoming EGFR-TKIs resistance in LUAD patients.

Dietary Habits and Breast Cancer Risk: A Hospital-Based Case-Control Study in Chinese Women.

PURPOSE: To investigate the relationship between dietary habits and breast cancer (BC) risk in Chinese women. PATIENTS AND METHODS: We performed a hospital-based matched case-control study that included 654 BC cases and 654 healthy controls matched by age and residence. A qualified structured questionnaire was used to collect detailed sociodemographic factors and information about dietary habits. The odds ratios (ORs) and 95% confidence intervals were calculated with unconditional logistic regression analysis; the patients were grouped according to their estrogen receptor (ER) status and analyzed separately. The propensity score analysis was performed according to different postmenopause status. RESULTS: ER-negative BC participants with intake of cured foods had increased BC risk (adjusted OR, 2.72, P = .017). Participants diagnosed as having ER-positive BC with intake of grilled foods had increased BC risk compared to those who did not consume such foods (adjusted OR, 2.14, P = .026). After propensity score analysis, fried (OR, 3.19, P = .001) and grilled (OR, 1.77, P = .031) food were considered to be risk factors for BC in premenopausal women; and fried (OR, 1.61, P = .006), grilled (OR, 4.62, P = .001), and smoked foods (OR, 2.28, P = .001) are considered risk factors for BC in postmenopausal women. CONCLUSION: Chinese women who ate cured, grilled, and fried foods had higher BC risk. Consumption of smoked food might contribute to increased BC risk in Chinese women.

Sur-X, a novel peptide, kills colorectal cancer cells by targeting survivin-XIAP complex.

BACKGROUND: Survivin and XIAP are two important members of the inhibitor of apoptosis protein family and have been considered as potential targets for cancer treatment due to their overexpression in large variety of cancers including colorectal cancer. It has been reported that survivin and XIAP can synergistically inhibit apoptosis by forming survivin-XIAP complex. In this study, we aimed to design a peptide that targets the survivin-XIAP complex and elucidate its anticancer mechanisms in colorectal cancer cells. METHODS: We designed and synthetized Sur-X, the peptide targeting survivin-XIAP complex. The anticancer effects of Sur-X were evaluated both in vitro and in vivo. The underlying molecular mechanisms were also investigated. RESULTS: Sur-X exhibited potent inhibitory effects on four colorectal cancer cell lines HCT116, HCT15, RKO and HT29, but not on human peritoneal mesothelial cell line HMrSV5. Mechanistically, Sur-X induced Caspase 9-dependent intrinsic apoptosis in colorectal cancer cells by disrupting the survivin-XIAP complex and subsequently destabilizing survivin and XIAP. Interestingly, we found that Sur-X can also promote necroptosis. It was demonstrated that Sur-X destroyed the interaction between XIAP and TAB1 in the XIAP-TAB1-TAK1 complex, leading to the instability of TAK1, an endogenous necroptosis inhibitor. Subsequently, the accelerated degradation of TAK1 attenuated its inhibition on necroptosis in colorectal cancer cells. Moreover, knockdown of TAK1 restored the sensitivity of TAB1-overexpressing colorectal cancer cells to Sur-X-induced necroptosis. The in vivo pro-apoptotic effect of Sur-X was confirmed by the enhanced TUNEL staining and the decreased expression of survivin and XIAP in tumor tissues from xenograft mouse models. In addition, extensive necrosis and weaker MLKL expression in xenografts provided evidence for the in vivo pro-necroptotic effect of Sur-X. CONCLUSIONS: Peptide Sur-X exhibits strong pro-apoptotic and pro-necroptotic effects in colorectal cancer cells and has a high clinical translation potential in the treatment of colorectal cancer.

Allium vegetables are associated with reduced risk of colorectal cancer: A hospital-based matched case-control study in China.

AIM: The present study aimed to investigate and identify the association between the intake of allium vegetables and colorectal cancer (CRC) in population. METHODS: A hospital-based matched case-control study was conducted between June 2009 and November 2011 in three hospitals. Eight hundred thirty three consecutively recruited cases of CRC were frequency matched to 833 controls by age (within 2.5 years of difference), sex, and residence area (rural/urban). Demographic and dietary information were collected via face-to-face interviews using a validated food frequency questionnaire. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated by using unconditional logistic regression. RESULTS: A decreased CRC risk was observed for the consumption of total (aORs of high total allium intake compared with low total allium intake = 0.21, 95% CI = 0.14-0.30, P trend <0.001) and several individual allium vegetables including garlic, garlic stalks, leek, onion, and spring onion (P trend <0.05). By further sex-stratified analysis, allium vegetable intake was demonstrated to be inversely associated with the risk of CRC in both men and women. However, the association of garlic intake with cancer risk was not significant among those with distal colon cancer (aOR = 0.53, 95% CI = 0.27-1.05, P trend = 0.248). CONCLUSION: In this analysis in a Northeast Chinese population, both men and women that the consumption of allium vegetables is associated with a reduced risk of CRC, regardless of colonic tumor subsite, with the exception of garlic intake in distal colon cancer.

Cruciferous vegetables and colorectal cancer risk: a hospital-based matched case-control study in Northeast China.

BACKGROUND/OBJECTIVES: Conflicting results have been reported on the association of cruciferous vegetable intake and colorectal cancer risk. This study aimed to clarify the relationship of cruciferous vegetables and colorectal cancer among individuals in Northeast China, where large amounts of cruciferous vegetables are consumed habitually. SUBJECTS/METHODS: We conducted a hospital-based case-control study in the First Hospital of China Medical University, the Shengjing Hospital of China Medical University and the First Hospital of Dalian Medical University from 2009 to 2011. Patients in the study were matched individually by age, gender, and city of residence. The study ultimately included 833 case-control pairs. A structured questionnaire was applied to collect data on general characteristics, dietary habits, and selected dietary intake. Differences between cases and controls were ascertained with the chi-square test or the Mann-Whitney U test. Unconditional logistic regression was employed to compute odds ratios (ORs) and 95% confidence intervals (CIs). Stratified analyses were conducted by gender. RESULTS: In the total study cohort, no significant association was found between total cruciferous vegetable intake and colorectal cancer risk. The adjusted OR for the highest versus the lowest intake was 0.83 (95% CI: 0.59-1.18). In stratification analyses by gender, reduced colorectal cancer risk was related to higher consumption of total cruciferous vegetables in women but not in men. Significant inverse correlations were found in analyses of individual cruciferous vegetables, including greens (OR = 0.47; 95% CI: 0.32-0.68), cabbage (OR = 0.61; 95% CI: 0.44-0.86), and cauliflower (OR = 0.66; 95% CI: 0.48-0.92). CONCLUSIONS: No significant association was found between total cruciferous vegetable intake and colorectal cancer risk. However, specific types of cruciferous vegetables might have protective roles against colorectal cancer.

Genomewide identification of a novel six-LncRNA signature to improve prognosis prediction in resectable hepatocellular carcinoma.

The current prognostic long noncoding RNA (lncRNA) signatures for hepatocellular carcinoma (HCC) are still controversial and need to be optimized by systematic bioinformatics analyses with suitable methods and appropriate patients. Therefore, we performed the study to establish a credible lncRNA signature for HCC outcome prediction and explore the related mechanisms. Based on the lncRNA profile and the clinical data of carefully selected HCC patients (n = 164) in TCGA, six of 12727 lncRNAs, MIR22HG, CTC-297N7.9, CTD-2139B15.2, RP11-589N15.2, RP11-343N15.5, and RP11-479G22.8 were identified as the independent predictors of patients' overall survival in HCC by sequential univariate Cox and 1000 times Cox LASSO regression with 10-fold CV, and multivariate Cox analysis with 1000 times bootstrapping. In the Kaplan-Meier analysis with patients trichotomized by the six-lncRNA signature, high-risk patients showed significantly shorter survival than mid- and low-risk patients (log-rank test P < 0.0001). According to the ROCs, the six-lncRNA signature showed superior predictive capacity than the two existing four-lncRNA combinations and the traditional prognostic clinicopathological parameter TNM stage. Furthermore, low MIR22HG and CTC-297N7.9, but high CTD-2139B15.2, RP11-589N15.2, RP11-343N15.5, and RP11-479G22.8, were, respectively, demonstrated to be related with the malignant phenotypes of HCC. Functionally, the six lncRNAs were disclosed to involve in the regulation of multiple cell cycle and stress response-related pathways via mediating transcription regulation and chromatin modification. In conclusion, our study identified a novel six-lncRNA signature for resectable HCC prognosis prediction and indicated the underlying mechanisms of HCC progression and the potential functions of the six lncRNAs awaiting further elucidation.