Effective oxygen metabolism-based prognostic signature for colorectal cancer.

Backgroud: Oxygen metabolism is an important factor affecting the development of tumors, but its roles and clinical value in Colorectal cancer are not clear. We developed an oxygen metabolism (OM) based prognostic risk model for colorectal cancer and explored the role of OM genes in cancer. Methods: Gene expression and clinical data obtained from The Cancer Genome Atlas, Clinical Proteomic Tumor Analysis Consortium databases were consider as discovery and validation cohort, respectively. The prognostic model based on differently expressed OM genes between tumor and GTEx normal colorectal tissues were constructed in discovery cohort and validated in validation cohort. The Cox proportional hazards analysis was used to test clinical independent. Upstream and downstream regulatory relationships and interaction molecules are used to clarify the roles of prognostic OM genes in colorectal cancer. Results: A total of 72 common differently expressed OM genes were detected in the discovery and validation set. A five-OM gene prognostic model including LRT2, ATP6V0E2, ODC1, SEL1L3 and VDR was established and validated. Risk score determined by the model was an independent prognostic according to routine clinical factors. Besides, the role of prognostic OM genes involves transcriptional regulation of MYC and STAT3, and downstream cell stress and inflammatory response pathways. Conclusions: We developed a five-OM gene prognostic model and study the unique roles of oxygen metabolism in of colorectal cancer.

Effects of somatic alterations at pathway level are more mechanism-explanatory and clinically applicable to quantity of liver metastases of colorectal cancer.

BACKGROUND: The quantity of metastases lesions is an important reference when it comes to making a more informed treatment decision for patients with colorectal cancer liver metastases. However, the molecular alterations in patients with different numbers of lesions have not been systematically studied. METHODS: We investigated somatic alterations and microsatellite instability (MSI) of liver metastases from patients with single, multiple or diffuse metastasis lesions. A new algorithm "Pathway Damage Score" was developed to comprehensively assess the functional impact of somatic alterations at the pathway level. Pathogenic pathways of different metastasis were identified and their prognosis effects were evaluated. Furthermore, the subnetworks and affected phenotypes of the altered genes in each pathogenic pathway were analyzed. RESULTS: Somatic alterations and altered genes occurred sporadically as well as in MSI state in different metastasis types, although MSS patients had more metastatic lesions than that of the MSI patients. Every metastasis group has their own pathogenic pathways and damaged "Cargo recognition for clathrin-mediated endocytosis" is significantly associated with poor prognosis (P < 0.001). Further pathway subnetwork analysis showed that except conventional drivers, other genes could also contribute to metastasis formation. CONCLUSIONS: Progression of liver metastasis could be driven by the coefficient of all altered genes belonging to the pathways. Thus, compared to somatic alterations and genes, pathway level analysis is more reasonable for functional interpretations of molecular alterations in clinical samples.

KDM5B promotes breast cancer cell proliferation and migration via AMPK-mediated lipid metabolism reprogramming.

Lysine demethylase 5B (KDM5B) is up-regulated in many cancers, including breast cancer. However, the underlying metabolic mechanisms of KDM5B on breast cancer progression are poorly understood. Here, we showed that KDM5B expression positively correlates with metastasis in breast cancer. Cell functional analyses were demonstrated that KDM5B knockdown and KDM5B inhibitor AS-8351 inhibited breast cancer cell proliferation and migration. Furthermore, we reported that KDM5B knockdown and AS-8351 reversed epithelial-mesenchymal transition (EMT) and decreased the protein levels of fatty acid synthase (FASN) and ATP citrate lyase (ACLY) in MCF-7 and MDA-MB-231 cells. Interestingly, we found that activation of AMP-activated protein kinase (AMPK) signaling pathway is involved in KDM5B-mediated EMT and lipid metabolism reprogramming in breast cancer cells. As a result, silencing of KDM5B-induced activation of AMPK signaling pathway inhibited breast cancer cell proliferation and migration. Taken together, our findings indicated that KDM5B was a novel regulator of lipid metabolism reprogramming, and it was suggested a new strategy to treat breast 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.

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.

Serum CA19-9 as a marker of circulating tumor cells in first reflux blood of colorectal cancer patients.

Circulating tumor cells (CTCs) are used for metastasis surveillance in cancer patients, but low detection rates limit their use in colorectal cancer (CRC). We investigated the distribution of CTCs in peripheral and portal blood of CRC patients, and analyzed the relationship between serum tumor CEA/CA19-9 markers and CTCs blood levels. CTC levels detected in first reflux/portal vein blood were higher than in peripheral blood, and liver reduced CTCs amount. CTCs-positive patients had increased serum CEA and CA 19-9 levels, and the CEA and CA 19-9 levels correlated with the CTCs levels. Even in non-metastatic CRC patients with barely detectable CTCs in peripheral blood, serum CA 19-9 levels correlated with the CTC levels in first reflux/portal vein blood. These results demonstrate that CTC detection in the first reflux vein/portal vein blood is more sensitive than in peripheral blood, suggesting that clinical diagnosis using the CellSearch System should be based on the CTC detection in first reflux vein blood due to the high detection rates. In addition, our results indicate that serum CA 19-9 levels may serve as a diagnostic marker for further evaluation of CTC levels in portal blood.

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.

UTX-1 regulates Tat-induced HIV-1 transactivation via changing the methylated status of histone H3.

Epigenetic modifications are thought to be important for gene expression changes during HIV-1 transcription and replication. The removal of histone H3 lysine27 (H3K27) trimethylation mark by UTX-1 is important for the robust induction of many specific genes during Tat-mediated HIV-1 transactvation. We found that UTX-1 enzymatic activity is needed for Tat to remove a repressive mark H3K27me3 in the HIV-1 long terminal repeat (LTR). UTX-1 converted the chromatin structure to a more transcriptionally active state by up-regulation of H3K4 methylation and down-regulation of H3K27 methylation on the specific regions of HIV-1 LTR. The increase in H3K27me3 and the decrease in H3K4me3 induced by UTX-1 knockdown was detected on the HIV-1 LTR, but not by control siRNA. Additionally, UTX-1 promotes HIV-1 gene expression by enhancing both the NF-κB p65's nuclear translocation and its p65 binding to HIV-1 LTR. And we further demonstrated that H3K27 demethylase activity was required for increased HIV-1 transactivation induced by UTX-1. Together, our data reveal key roles for UTX-1 in a timely transition from poised to active chromatin in HIV-1 LTR during HIV-1 transcription and a fundamental mechanism by which a H3K27 demethylase triggers tissue-specific chromatin changes. Our findings provide a mechanistic link between UTX-1 and enhanced HIV-1 replication, and suggest that targeting at epigenetic mechanism may have a therapeutic benefit for HIV-1 patients.

Cardenolides from the bark of Calotropis gigantea.

Three new cardenolides (1-3) were isolated from the 90% ethanolic extract of the bark of a wild-type Calotropis gigantea. Their structures were determined by using NMR spectra and LC-MS analysis. Their inhibitory activities were evaluated against non-small cell lung carcinoma (A549) and human cervix epithelial adenocarcinoma (HeLa) cell lines. Compounds 1 and 3 exhibited strong inhibitory effect on two cancer cell lines.

Adsorption removal of phosphate from aqueous solution by active red mud.

Red mud is the waste of alumina industry and has high TiO2 and Fe2O3 content which are active components for the adsorption of anion pollutants. In this study, the uptake of phosphate by red mud activated by heat treatment and acid-heat treatment was investigated. The factors influencing the adsorption were also investigated. The result showed that the red mud sample treated using acid-heat method at 80 degrees C with 0.25 mol/L HCl for 2 h achieved the highest phosphate removal. For the heat-activated red mud, the sample heated at 700 degrees C for 2 h preformed better than the other heat treatment. Phosphate removal by the activated red mud was significantly pH dependent, and pH 7 was the optimal pH for phosphate removal. The adsorption fits Langmuir isotherm model well and the maximum adsorption capacities of the acid-heat activated red mud and the heat activated samples were 202.9 mgP/g and 155.2 mgP/g, respectively.

[Breakage and regrowth of flocs coagulation with polyaluminum chloride (PACl)].

The conventional jar test and the monitoring technique of floc size in line were employed to investigate the breakage and regrowth of the flocs formed by PACl. It was found that the breakage and regrowth of flocs varied with coagulation zones. The flocs formed in stabilization zone were of high strength and difficult to break, and could regrow better after broken, with the recovery factor of up to 259%. The flocs formed in charge neutralization zone were of the lowest strength and prone to break, but could reform completely after broken. The flocs formed in restabilization and sweep coagulation zones were also of high strength and difficult to break, but significantly irreversible after broken. The recovery factor of the broken flocs in sweep coagulation zone was only 18.6%. The effects of remixing on the breakage and regrowth of flocs increased with remixing intensity. In sweep coagulation zone, the settling height and mean settling velocity of the interface between flocs blanket and water were lower for the broken and partly reforming flocs than for those unbroken; Moreover, in flocculation settling and zone settling zones, the instantaneous settling velocity of the interface at the same flocs concentration was also lower for the broken flocs than for those unbroken, but in compression settling zone, the instantaneous settling velocity was the same whether the flocs were broken or not.

[Electrochemical hydrodehalogenation of pentachloraphenol in aqueous solution by porous titanium loaded Pd cathode].

A study on electrochemical hydrodehalogenation of pentachloraphenol in aqueous solutions was conducted on porous titanium loaded Pd cathode and the operational parameters were investigated. Chloride ions and phenol is the main products analyzed by GC-MS. Up to 100% electrochemical hydrodehalogenation can be achieved with more than 90% conversion to phenol. The result showed that current in the circle play the most important role of dehalogenation while the best parameter is 300mA in this study. Compared to current, the effect of pH value and flow rate on the current efficiency and energy consumption of dehalogenation is limited. Complete dehalogenation, high current efficiency, low energy consumption and operational convenience confirm the feasibility of this method.

[Treatment efficacy of surgical management for liver metastasis from colorectal cancer--a report of 198 cases].

BACKGROUND & OBJECTIVE: Liver is the most common site of metastasis in colorectal cancer, and 35% patients with colorectal cancer developed liver metastasis at diagnosis. The prognosis of the patients with liver metastases from colorectal cancer is poor. Surgical resection, radiofrequency ablation, and chemotherapy had been used in clinical treatment for liver metastasis from colorectal cancer with various outcomes. This study was to explore the treatment efficacy of surgical management for liver metastasis from colorectal cancer. METHODS: Clinical data of 198 patients with liver metastasis from colorectal cancer, treated from Jan. 1995 to Jan. 2000, were studied retrospectively. Of the 198 patients, 46 (23.2%) received radical resection, 43 (21.7%) received palliative resection, 29 (14.6%) received exploratory operation or supportive treatment, 41 (20.7%) received adjuvant hepatic arterial infusion, and 39 (19.7%) received adjuvant systemic chemotherapy. Survival statuses of the patients in different groups were compared. RESULTS: The median survival time of radical resection group was significantly longer than those of palliative resection group, exploratory operation or supportive treatment group, adjuvant hepatic arterial infusion group, and adjuvant systemic chemotherapy group (37.1 months vs. 14.3, 6.3, 21.3, and 18.7 months, P<0.01). The 5-year survival rates of the 5 groups were 31.2%, 0, 0, 7.5%, and 0, respectively. CONCLUSIONS: Radical resection could improve survival of the patients with liver metastasis from colorectal cancer. Palliative resection has no advantage over adjuvant therapy. Adjuvant hepatic arterial infusion should be applied in the unresectable cases.

[Clinical research of synchronous colorectal neoplasms].

OBJECTIVE: To investigate the clinical and pathological features of synchronous colorectal carcinomas and explore the specificity of treatment for those patients. METHODS: A retrospective evaluation of 326 patients with primary colorectal cancer were performed. The patients were divided into two groups: single cases (303 patients) and synchronous cases (23 patients, index cancer and second cancer). Clinical characteristics, routine pathological findings in the two groups were compared statistically. RESULTS: There was no difference in location of the lesions between the single cases and the index lesions of synchronous cases, while the differentiation and Ducke stage of index lesions were better than those in single cases. The secondary cancer of synchronous cases showed better grades and stages than those of single cases. The frequencies of complicating adenoma and multiple polyps in synchronous cases were higher significantly than those in single cases, with the rate of 34.8% and 78.3%, 11.6% and 42.2%, respectively. All malignant lesions were resected radically, and multiple polyps (56.9%) were electro-resected under colonoscopy at 2 approximately 3 months after the carcinomas were radically resected. Of the patients complicated with adenomas, 79.1% (34 cases) were given one-stage local resection or local colectomy and the rest were given second stage electro-resection. CONCLUSIONS: For the clinical and pathological features of synchronous colorectal carcinomas, it is essential to perform a complete evaluation of all colorectal lesions, establish an individual surgical treatment and follow-up in time.

Performance of a novel vertical-flow settler: a comparative study.

By increasing particle concentration and G value (root-mean-square velocity gradient) to enhance flocculation, a novel vertical-flow settler was designed to increase sedimentation effectiveness, and to simultaneously improve operational stabilization. Due to the gradual decrease in upward flow-rate of raw water, a flocs blanket would form and suspend in the middle section of the settler, not at the bottom as in a conventional clarifier. Enough large flocs, resulted from flocculation or filtration, would continuously settle out of the flocs blanket, and simultaneously, the flocs in raw water or those forming above the blanket would ceaselessly enter the flocs blanket. As a result, the flocs concentration in the blanket could keep a dynamic balance. The hydrodynamic shear in the blanket was improved by flow separation, which was induced by the abrupt change in flow channel. Due to the floes blanket and improved hydrodynamic shear, flocculation would be enhanced, which was helpful for removing fine particles in raw water. A comparative study showed that the novel vertical-flow settler had a much better performance in the removal of the particles in raw water than a conventional one, when they treated kaolin suspensions of different concentrations (500, 100 and 50 mg/L, respectively) coagulated by polyaluminum chloride(PAC1) at the up-flow rates of I and 2 mm/s, respectively.

[Diagnosis and treatment of 41 patients with malignant peritoneal mesothelioma].

OBJECTIVE: To study the methods of diagnosis and treatment of malignant peritoneal mesothelioma. METHODS: The clinical data of 41 patients with malignant peritoneal mesothelioma pathologically confirmed were retrospectively analyzed. RESULTS: Of these 41 patients, abdominal pain and diarrhea were found in 38 and 35. The histopathologic types were: epitheloid, fusiform and mixed in 21, 11 and 9 cases. CT was performed in 21 and laparoscopic exploration in 13. The overall surgical resection rate was 70.7%. After operation, local abdominal cavity chemotherapeutic instillation was given in 12, systemic chemotherapy in 23 and immunotherapy in 3. The two year survival rate was 36.6%. CONCLUSION: For malignant peritoneal mesothelioma, the final diagnosis depends on histological examination and the treatment should be surgical-core combined methods.