Awareness, attitude and barriers of colorectal cancer screening among high-risk populations in China: a cross-sectional study.

OBJECTIVE: To assess the awareness, attitude and barriers of colorectal cancer screening among high-risk populations in China. DESIGN: A cross-sectional study was employed. SETTING: This study was conducted in nine hospitals in Hunan province, China. PARTICIPANTS: Individuals with a high-risk for colorectal cancer were interviewed using a pretested structured questionnaire. PRIMARY AND SECONDARY OUTCOME MEASURES: Knowledge, attitude towards colorectal cancer screening, sociodemographic factors associated with screening knowledge and behaviour and barriers of colorectal cancer screening. RESULTS: This study included 684 participants. The mean knowledge score was 11.86/24 (SD 4.84). But over 70% of them held a positive attitude towards screening. Only 13.3% had undergone colorectal cancer screening. Independent factors related to knowledge were education level of college or above, working as a white collar, higher income, having health insurance, having seen a doctor in the past year and with a high perceived risk (p<0.05). Factors independently associated with screening behaviour included personal history of colorectal disease, having seen a doctor in the past year, previous discussion of colorectal cancer screening, high perceived risk and better knowledge (p<0.05). Main reasons for not undergoing screening were no symptoms or discomfort (71.1%), never having thought of the disease or screening (67.4%) and no doctor advised me (29.8%). CONCLUSION: In China, the majority of high-risk people had deficient knowledge and had never undergone colorectal cancer screening. But most of them held a positive attitude towards the benefits of colorectal cancer screening. This has promising implications to design targeted educational campaigns and establish screening programmes to improve colorectal cancer awareness and screening participation. Healthcare professionals should advise high-risk individuals to participate in screening and inform them about cancer risk.

Fusion of macrophages promotes breast cancer cell proliferation, migration and invasion through activating epithelial-mesenchymal transition and Wnt/ß-catenin signaling pathway.

Cell fusion is a highly regulated process involved in cancer development, tissue regeneration and other physiological and pathological events. Many studies have shown that cancer cells can fuse with different types of cells such as mesenchymal stem cells (MSCs) and macrophages, which are behaved as two important fusogenic candidates in the tumor microenvironment. However, the underlying mechanisms of cell fusion between macrophages and malignant cells in cancer progression has not been fully clarified. The aim of the present study was to investigate the effects and mechanisms of cell fusion between macrophages and breast cancer cells on tumorigenesis and metastasis. Our results indicated that the hybrids exhibited enhanced proliferation, colony formation, migration and invasion capabilities, as well as suppressed apoptosis compared with parental breast cancer cells. Moreover, the hybrid cells displayed EMT with a significant downregulation of E-cadherin and upregulation of N-cadherin, Vimentin and Snail, as well as an obviously increased expression of MMP-2, MMP-9, uPA and S100A4. Mechanistically, we found that the TCF/LEF transcription factor activity of Wnt/ß-catenin pathway and the expression of its downstream target genes including cyclin D1 and c-Myc were increased in the hybrid cells. Furthermore, our data confirmed that the promoting effects of fusion of macrophages on breast cancer cell proliferation, migration and invasion could be blocked by treatment with XAV-939, a Wnt/ß-catenin signaling pathway inhibitor. In conclusion, our findings demonstrate that fusion of macrophages promotes proliferation, migration and invasion of breast cancer cells through activating EMT and Wnt/ß-catenin signaling pathway. Our current study will further contribute to elucidate the mechanism of cell fusion in tumorigenesis and metastasis, and to develop a new therapeutic strategy for breast cancer treatment.

Awareness of risk factors and warning symptoms and attitude towards gastric cancer screening among the general public in China: a cross-sectional study.

OBJECTIVES: This study aimed to assess the knowledge of risk factors and warning symptoms and attitude towards gastric cancer screening among the general population in China. SETTING: Hunan province, China PARTICIPANTS: Individuals aged older than 18 years were recruited using a cluster sampling method. DESIGN: A cross-sectional study, and a pretested structured questionnaire was used to assess participants' awareness of gastric cancer. PRIMARY AND SECONDARY OUTCOME MEASURES: Knowledge level of risk factors and warning symptoms of gastric cancer, gastric cancer screening attitude, sociodemographic factors associated with gastric cancer knowledge and screening behaviour. RESULTS: This study comprised 1200 participants with a mean age of 40.31 (SD 16.73) years, of whom 622 (51.8%) were women. The mean score for gastric cancer knowledge was 8.85/22 (SD 6.48). There were 47.0% of the participants who had a low knowledge level about the risk factors and warning symptoms of gastric cancer. In total, 83.8% believed screening is helpful for early detection of gastric cancer, and 15.2% had undergone gastric cancer screening. The most common reason for not undergoing screening was having 'no symptoms' (63.0%), followed by 'fear of undergoing gastroscopy' (38.1%). Independent factors related to lower knowledge levels included male sex, living in rural areas, lower educational level, working as a farmer and without a family history of gastric cancer (p<0.05). Factors independently associated with screening behaviour included white-collar employment, higher income and having upper gastrointestinal tract diseases (p<0.05). CONCLUSIONS: In China, people have poor knowledge about risk factors and warning symptoms of gastric cancer, but a majority have a positive attitude towards the benefits of gastric cancer screening. Being asymptomatic and having a fear of gastroscopy were the main self-reported reasons for not undergoing screening. These results highlight the urgent need for educational campaigns to improve gastric cancer awareness.

Loss of G3BP1 suppresses proliferation, migration, and invasion of esophageal cancer cells via Wnt/ß-catenin and PI3K/AKT signaling pathways.

Accumulating evidence suggests that Ras GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is very crucial to regulate tumorigenesis and metastasis. Recently, many research works have suggested that G3BP1 is overexpressed in many human cancers including esophageal cancer. Nevertheless, the functional roles of G3BP1 in esophageal cancer are still unknown. Here, the results suggested that silencing of G3BP1 inhibited proliferation, migration, and invasion of esophageal cancer cells, whereas overexpression of G3BP1 led to opposite effects on the growth and metastasis. Surprisingly, G3BP1-depletion had no effect on cell death but caused the arrest of cell cycle in the G0 /G1 phase and increased the levels of p53 and p21. In addition, loss of G3BP1 led to a significant elevation of E-cadherin and decrease of N-cadherin, Vimentin, Snail, MMP-9, and MMP-2. Mechanistically, loss of G3BP1 dramatically suppressed Wnt-stimulated T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor activity and downregulated its target genes including c-Myc, Axin2, and cyclin D1. Moreover, knockdown of G3BP1 downregulated the expression levels of p-PI3K, p-AKT, and p-GSK-3ß, but the total PI3K, AKT, and GSK-3ß were not changed. Furthermore, our data proved that the promoting effects of G3BP1-overexpression on cell proliferation, migration, and invasion could be rescued by PI3K inhibitor LY294002 treatment. Collectively, our results here elucidate that G3BP1-depletion suppresses proliferation, migration, and invasion capabilities of esophageal cancer cells via the inactivation of Wnt/ß-catenin and PI3K/AKT signaling pathways. Furthermore, our findings imply that G3BP1 can participate in the regulation of esophageal cancer progression, and will be taken as a promising target to treat esophageal cancer.

Nrf2 promotes breast cancer cell migration via up-regulation of G6PD/HIF-1α/Notch1 axis.

Abnormal metabolism of tumour cells is closely related to the occurrence and development of breast cancer, during which the expression of NF-E2-related factor 2 (Nrf2) is of great significance. Metastatic breast cancer is one of the most common causes of cancer death worldwide; however, the molecular mechanism underlying breast cancer metastasis remains unknown. In this study, we found that the overexpression of Nrf2 promoted proliferation and migration of breast cancers cells. Inhibition of Nrf2 and overexpression of Kelch-like ECH-associated protein 1 (Keap1) reduced the expression of glucose-6-phosphate dehydrogenase (G6PD) and transketolase of pentose phosphate pathway, and overexpression of Nrf2 and knockdown of Keap1 had opposite effects. Our results further showed that the overexpression of Nrf2 promoted the expression of G6PD and Hypoxia-inducing factor 1α (HIF-1α) in MCF-7 and MDA-MB-231 cells. Overexpression of Nrf2 up-regulated the expression of Notch1 via G6PD/HIF-1α pathway. Notch signalling pathway affected the proliferation of breast cancer by affecting its downstream gene HES-1, and regulated the migration of breast cancer cells by affecting the expression of EMT pathway. The results suggest that Nrf2 is a potential molecular target for the treatment of breast cancer and targeting Notch1 signalling pathway may provide a promising strategy for the treatment of Nrf2-driven breast cancer metastasis.

Loss of HACE1 promotes colorectal cancer cell migration via upregulation of YAP1.

Colorectal cancer (CRC) is the third-leading cause of cancer mortality worldwide. HACE1 function as a tumor-suppressor gene and is downregulated in several kinds of cancers. However, the distribution and clinical significance of HACE1 in CRC is still not clarified. In this study, we found that the HACE1 expression is greatly downregulated in CRC tissues and cell lines. Moreover, the HACE1 expression was significantly associated with inhibition of CRC cell proliferation, metastasis, and invasion. HACE1 inhibited epithelial-mesenchymal transition in CRC cells. Furthermore, we found that HACE1 altered the protein expression of the Hippo pathway by downregulation of YAP1. HACE1 suppresses the invasive ability of CRC cells by negatively regulating the YAP1 pathway. Our data indicates that HACE1 directly targets YAP1 and induces downregulation of YAP1, thereby increasing the activity of the Hippo pathway. In summary, these findings demonstrated that HACE1-YAP1 axis had an important part in the CRC development and progression.

Fusion with mesenchymal stem cells differentially affects tumorigenic and metastatic abilities of lung cancer cells.

Cell fusion plays a crucial role in cancer progression and leads to massive aberrant changes in chromosome and gene expression involved in tumor metastasis. Cancer cells can fuse with many cell types, including stromal cells, epithelial cells, macrophages, and endothelial cells. Mesenchymal stem cells (MSCs) have been reported to migrate and incorporate into tumor sites during cancer progression. However, the underlying mechanism of stem cell fusion in tumor metastasis has not been fully deciphered. In this research, we established a cell fusion model between lung cancer cells and MSCs in vitro. We found that the hybrid cells showed enhanced metastatic capacity with increased expression of MMP-2 and MMP-9, whereas the proliferation ability was inhibited and cell cycle was blocked in the G0 /G1 phase with elevated expression of p21, p27, and p53. Moreover, the hybrid cells lost epithelial morphology and exhibited an epithelial-mesenchymal transition (EMT) change with downregulation of E-cadherin and upregulation of N-cadherin, Vimentin, α-SMA and Fibronectin1. Meanwhile, the expressions of EMT transcription factors, including Snail1, Slug, Twist1, Zeb1, and Zeb2, were also increased in hybrid cells. More important, the fusion hybrids acquired stem cell-like properties, which exhibited increased expression stem cell transcription factors Oct4, Sox2, Nanog, Kif4 as well as Bmi1. Taken together, our results suggested that cell fusion between lung cancer cells and MSCs offered enhanced metastatic capacity and characteristics of cancer stem cell by undergoing EMT. This study will contribute to explaning the origin of lung cancer stem cells and to elucidate the role of cell fusion in cancer metastasis.

NRF2 facilitates breast cancer cell growth via HIF1ɑ-mediated metabolic reprogramming.

High aerobic glycolysis not only provides energy to breast cancer cells, but also supports their anabolic growth. The redox sensitive transcription factor NRF2 is over-expressed in multiple cancers, including breast cancer. It is unclear whether NRF2 could promote breast cancer cell growth through enhancing glycolysis. In this study, we found that NRF2 and HIF1α mRNA and protein levels were significantly increased in MCF-7 and MDA-MB-231 breast cancer cells as compared to MCF-10A benign breast epithelial cells. Down-regulation of NRF2 decreased MCF7 and MBA-DA-231 breast cell proliferation, while it reversed by hypoxia inducible factor 1α (HIF1α). Knockdown of NRF2 inhibited glycolysis by decreasing the expression of genes participated in glucose metabolism, including HK2, PFKFB3, PKM2 and LDHA. Our results further indicated that the AKT activation and AMPK inhibition were required for NRF2-mediated up-regulation of glycolytic enzymes. Consistent with these results, a positive correlation existed between NRF2 or HIF1α and several key glycolytic genes in human breast cancer cell samples and breast cancer patients with high NRF2 or HIF1α expression had poorer overall survival. In conclusion, our study demonstrates that NRF2 promotes breast cancer progression by enhancing glycolysis through coactivation of HIF1α, implicating that NRF2 is a potential molecular target for breast cancer treatment.

Loss of TET1 facilitates DLD1 colon cancer cell migration via H3K27me3-mediated down-regulation of E-cadherin.

Epigenetic modifications such as histone modifications and cytosine hydroxymethylation are linked to tumorigenesis. Loss of 5-hydroxymethylcytosine (5 hmC) by ten-eleven translocation 1 (TET1) down-regulation facilitates tumor initiation and development. However, the mechanisms by which loss of TET1 knockdown promotes malignancy development remains unclear. Here, we report that TET1 knockdown induced epithelial-mesenchymal transition (EMT) and increased cancer cell growth, migration, and invasion in DLD1 cells. Loss of TET1 increased EZH2 expression and reduced UTX-1 expression, thus increasing histone H3K27 tri-methylation causing repression of the target gene E-cadherin. Ectopic expression of the H3K27 demethylase UTX-1 or EZH2 depletion both impeded EZH2 binding caused a loss of H3K27 methylation at epithelial gene E-cadherin promoter, thereby suppressing EMT and tumor invasion in shTET1 cells. Conversely, UTX-1 depletion and ectopic expression of EZH2 enhanced EMT and tumor metastasis in DLD1 cells. These findings provide insight into the regulation of TET1 and E-cadherin and identify EZH2 as a critical mediator of E-cadherin repression and tumor progression.

PKM2-mediated inhibition of autophagy facilitates Tat's inducing HIV-1 transactivation.

Considerable evidence has shown that autophagy has an important role in HIV-1 infection. However, it is still unknown whether metabolism-regulated autophagy pathway is involved in Tat-mediated HIV-1 transactivation. This study demonstrated that treatment of Tat in TZM-bl cells significantly down-regulated protein levels of Beclin-1, Atg-5, Atg-7, and LC3B-II and up-regulated of p62 levels. Blockage of autophagy enhanced Tat-induced HIV-1 transactivation in TZM-bl cells. Moreover, we found that Tat activated the Akt/mTOR and inhibited AMPK signaling pathway that was related to its up-regulation of PKM2 expression. In addition, we showed that PI3K/AKT activation and AMPK inhibtion was required for the PKM2-mediated inhibition of autophagy in Tat-treated TZM-bl cells. In conclusion, our data reveals that PKM2-mediated autophagy inhibition is required for Tat-mediated HIV-1 transactivation. Metabolism-related autophagic pathway may act as a promising diagnostic and therapeutic tool for HIV-1 infection in the future.

Tanshinone â ¡A inhibits human esophageal cancer cell growth through miR-122-mediated PKM2 down-regulation.

Pyruvate kinase M2 (PKM2) plays a pivotal role in the growth, survival and metabolic reprogramming of cancer cells. Here, we presented for the first time that tanshinone ⅡA inhibited human esophagus cancer cell growth through miR-122-mediated PKM2 down-regulation pathway. Tanshinone ⅡA inhibited cell proliferation and induced cell cycle arrest in S phase in human Ec109 cells. As expected, tanshinone ⅡA down-regulated PKM2 mRNA and protein expression in Ec109 cells. Given these findings, we further investigated microRNAs regulation of PKM2 and confirmed miR-122 for targeting PKM2. Moreover, we found that tanshinone ⅡA-induced up-regulation of miR-122 expression inhibited PKM2 expression in Ec109 cells. Meanwhile, tanshinone ⅡA inhibited proliferation through miR122-medated PKM2 down-regulation. It was demonstrated that the anticancer activity of tanshinone ⅡA was targeted at metabolic regulation of miR-122/PKM2 in human esophagus cancer cells. Taken together, our results revealed tanshinone ⅡA targeting at PKM2-mediated metabolic reprogramming play an important role in inhibition of esophageal cancer cell growth.

Curcumin inhibits Ec109 cell growth via an AMPK-mediated metabolic switch.

AIMS: Glycolytic enzymes are always greatly increased in cancer cells. Whether metabolic reprogramming is involved in curcumin-mediated inhibition of cancer cell growth is unknown. MAIN METHODS: In this study, cell viability was assayed with MTS analysis; cell cycle was measured with flow cytometry analysis. RT-PCR and western blotting were used to analyse the mRNA and protein expression, respectively. KEY FINDINGS: Here we demonstrated that curcumin inhibited cancer cell growth, especially for Ec109 cells. Curcumin induced cell cycle arrest at G2/M phase. Curcumin caused a significant down-regulation of glycolytic enzymes expressions in a dose-dependent manner. Our results further indicated that the AMPK was required for curcumin-mediated down-regulation of glycolytic enzymes. AMPK-mediated down-regulation of glycolytic enzymes blocked Ec109 cell growth. SIGNIFICANCE: Taken together, our results revealed that the AMPK-mediated metabolic switch plays an important role in esophageal cancer cell growth.

Understanding and targeting cancer stem cells: therapeutic implications and challenges.

Cancer stem cells (CSCs) have been identified as rare cell populations in many cancers, including leukemia and solid tumors. Accumulating evidence has suggested that CSCs are capable of self-renewal and differentiation into various types of cancer cells. Aberrant regulation of gene expression and some signaling pathways has been observed in CSCs compared to other tumor cells. CSCs are thought to be responsible for cancer initiation, progression, metastasis, recurrence and drug resistance. The CSC hypothesis has recently attracted much attention due to the potential for discovery and development of CSC-related therapies and the identification of key molecules involved in controlling the unique properties of CSC populations. Over the past several years, a tremendous amount of effort has been invested in the development of new drugs, such as nanomedicines, that can take advantage of the "Achilles' heel" of CSCs by targeting cell-surface molecular markers or various signaling pathways. Novel compounds and therapeutic strategies that selectively target CSCs have been identified, some of which have been evaluated in preclinical and clinical studies. In this article, we review new findings related to the investigation of the CSC hypothesis, and discuss the crucial pathways involved in regulating the development of CSC populations and the advances in studies of drug resistance. In addition, we review new CSC-targeted therapeutic strategies aiming to eradicate malignancies.

Phosphorylation of Rad9 at serine 328 by cyclin A-Cdk2 triggers apoptosis via interfering Bcl-xL.

Cyclin A-Cdk2, a cell cycle regulated Ser/Thr kinase, plays important roles in a variety of apoptoticprocesses. However, the mechanism of cyclin A-Cdk2 regulated apoptosis remains unclear. Here, we demonstrated that Rad9, a member of the BH3-only subfamily of Bcl-2 proteins, could be phosphorylated by cyclin A-Cdk2 in vitro and in vivo. Cyclin A-Cdk2 catalyzed the phosphorylation of Rad9 at serine 328 in HeLa cells during apoptosis induced by etoposide, an inhibitor of topoisomeraseII. The phosphorylation of Rad9 resulted in its translocation from the nucleus to the mitochondria and its interaction with Bcl-xL. The forced activation of cyclin A-Cdk2 in these cells by the overexpression of cyclin A,triggered Rad9 phosphorylation at serine 328 and thereby promoted the interaction of Rad9 with Bcl-xL and the subsequent initiation of the apoptotic program. The pro-apoptotic effects regulated by the cyclin A-Cdk2 complex were significantly lower in cells transfected with Rad9S328A, an expression vector that encodes a Rad9 mutant that is resistant to cyclin A-Cdk2 phosphorylation. These findings suggest that cyclin A-Cdk2 regulates apoptosis through a mechanism that involves Rad9phosphorylation.