Inactivation of KDM6A promotes the progression of colorectal cancer by enhancing the glycolysis.

KDM6A (lysine demethylase 6A) has been reported to undergo inactivating mutations in colorectal cancer, but its function in the progression of colorectal cancer has not been evaluated using animal models of colorectal cancer. In this study, we found that knocking out KDM6A expression in mouse intestinal epithelium increased the length of villus and crypt, promoting the development of AOM (azoxymethane)/DSS (dextran sulfate sodium salt)-induced colorectal cancer. On the other hand, knocking down KDM6A expression promoted the growth of colorectal cancer cells. In molecular mechanism studies, we found that KDM6A interacts with HIF-1α; knocking down KDM6A promotes the binding of HIF-1α to the LDHA promoter, thereby promoting LDHA expression and lactate production, enhancing glycolysis. Knocking down LDHA reversed the malignant phenotype caused by KDM6A expression loss. In summary, this study using animal models revealed that KDM6A loss promotes the progression of colorectal cancer through reprogramming the metabolism of the colorectal cancer cells, suggesting that restoring the function of KDM6A is likely to be one of the strategies for colorectal cancer treatment.

Phosphorylation of PPDPF via IL6-JAK2 activates the Wnt/ß-catenin pathway in colorectal cancer.

Inflammation plays an important role in the initiation and progression of colorectal cancer (CRC) and leads to ß-catenin accumulation in colitis-related CRC. However, the mechanism remains largely unknown. Here, pancreatic progenitor cell differentiation and proliferation factor (PPDPF) is found to be upregulated in CRC and significantly correlated with tumor-node-metastasis (TNM) stages and survival time. Knockout of PPDPF in the intestinal epithelium shortens crypts, decreases the number of stem cells, and inhibits the growth of organoids and the occurrence of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC. Mechanistically, PPDPF is found to interact with Casein kinase 1α (CK1α), thereby disrupting its binding to Axin, disassociating the ß-catenin destruction complex, decreasing the phosphorylation of ß-catenin, and activating the Wnt/ß-catenin pathway. Furthermore, interleukin 6 (IL6)/Janus kinase 2 (JAK2)-mediated inflammatory signals lead to phosphorylation of PPDPF at Tyr16 and Tyr17, stabilizing the protein. In summary, this study demonstrates that PPDPF is a key molecule in CRC carcinogenesis and progression that connects inflammatory signals to the Wnt/ß-catenin signaling pathway, providing a potential novel therapeutic target.

A Nomogram for Predicting the Cancer-Specific Survival of Patients with Initially Diagnosed Metastatic Gastric Cancer.

Background: There are few models to predict the survival of patients of different ethnicities initially diagnosed with metastatic gastric cancer (mGC). Therefore, the aim of this study was to construct a nomogram to predict the cancer-specific survival (CSS) of these patients. Methods: Data for 994 patients initially diagnosed with mGC between 2000 and 2013 were extracted from the Surveillance, Epidemiology, and End Results database. Patients were randomly classified into a training (n = 696) or internal validation (n = 298) cohort, and a cohort of 133 patients from Fudan cohort was used for external validation. A nomogram to predict the CSS of mGC patients was derived and validated using a concordance index (C-index), calibration curves, and decision-curve analysis (DCA). Results: Multivariate Cox regression indicated that five factors were independent predictors of CSS: differentiation grade, T stage, N stage, metastatic site at diagnosis, and with or without chemotherapy. Thus, these factors were integrated into the nomogram model. The C-index value of the nomogram model was 0.63 (95% CI: 0.60-0.65), and those of the internal and external validation cohorts were 0.60 (95%: CI 0.55-0.64) and 0.63 (95%: CI 0.57-0.69), respectively. The calibration curves showed good consistency between the actual and predicted survival rates in both the internal and external validation cohorts. The DCA also showed the clinical utility of the nomogram model. Conclusions: We established a practical nomogram to predict the CSS of patients initially diagnosed with mGC. The nomogram can be used for individualized prediction of survival and to guide clinicians in making treatment decisions.

TFCP2 Overcomes Senescence by Cooperating With SREBP2 to Activate Cholesterol Synthesis in Pancreatic Cancer.

KRAS mutation is very common in pancreatic cancer. How pancreatic cancer cells overcome oncogene-induced senescence is not fully understood. Our previous studies showed that up-regulation of TFCP2 (transcription factor CP2) in pancreatic cancer promoted the growth and metastasis of pancreatic cancer cells. However, whether TFCP2 plays an important role in pancreatic cancer cell senescence is not clear. In this study, we found upregulation of TFCP2 expression in pancreatic cancer was associated with KRAS mutation. Overexpression of TFCP2 inhibited cell senescence. Knockdown of TFCP2 promoted cell senescence. Mechanistically, the interaction between TFCP2 and SREBP2 (sterol regulatory element binding transcription factor 2) synergistically activated the expression of HMGCR, a rate-limiting enzyme in cholesterol synthesis, and statins could reverse the inhibitory effect of TFCP2 on senescence. In conclusion, our study reveals a new mechanism underlying the TFCP2 regulation of pancreatic cancer cell senescence, providing a new target for the treatment of pancreatic cancer.

LINC00961 inhibits the migration and invasion of colon cancer cells by sponging miR-223-3p and targeting SOX11.

Long noncoding RNAs play essential roles in colon cancer tumorigenesis. This study aimed to explore the potential function and molecular mechanisms of LINC00961 in colon cancer. qPCR results showed that LINC00961 was downregulated in colon cancer cells and tissues. Functional assays demonstrated that LINC00961 suppressed the migration and invasion of colon cancer cells in vitro. LINC00961 functioned as an endogenous sponge for miR-223-3p in colon cancer cells. SOX11 was confirmed as a target gene of miR-223-3p. The effect of miR-223-3p on colon cancer cells was then investigated. MiR-223-3p inhibition enhanced their migration and invasion. The effect of SOX11 on colon cancer cells was studied. SOX11 overexpression inhibited the invasion of colon cancer cells. LINC00961 acted as an anti-oncogene and upregulated SOX11 expression by functioning as a miR-223-3p sponge. This research revealed the molecular mechanism of LINC00961 in colon cancer. LINC00961 might act as a potential diagnostic biomarker and therapeutic target for further clinical treatments.

Loss of FOXN3 in colon cancer activates beta-catenin/TCF signaling and promotes the growth and migration of cancer cells.

Aberrant activation of beta-catenin/TCF is a hallmark of colon cancer. How the functions of nuclear localized beta-catenin are regulated is not fully understood. Here, it was found that FOXN3 (Forkhead box N3) was down-regulated in colon cancer tissues. Forced expression of FOXN3 inhibited the growth, migration and invasion of colon cancer cells, while knocking down the expression of FOXN3 promoted the growth, migration, invasion and metastasis of colon cancer cells. FOXN3 bind to beta-catenin and inhibited beta-catenin/TCF signaling by blocking the interaction between beta-catenin and TCF4. Taken together, these data demonstrated the suppressive roles of FOXN3 in the progression of colon cancer, and indicated that restoring the functions of FOXN3 would be a novel therapeutic strategy for colon cancer.

PEBP4 promoted the growth and migration of cancer cells in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignancies in the world. Numerous studies have linked the activation of AKT to the progression of PDAC. Phosphatidylethanolamine-binding protein 4 (PEBP4) has been reported to be upregulated in various cancer types. However, its expression pattern and biological functions in PDAC are unknown. In this study, it was found that the messenger RNA (mRNA) and protein level of PEBP4 was elevated in PDAC samples. Forced expression of PEBP4 in PDAC cell lines promoted cell growth and migration, while downregulation of PEBP4 in PDAC cells by RNA interference (RNAi) inhibited the growth, migration, and metastasis of the cancer cells. PEBP4 interacted with AKT and promoted the phosphorylation of serine 473 in AKT. Collectively, this study suggested that PEBP4 might promote the progression of PDAC through activating AKT signaling and PEBP4 might be a promising therapeutic target for PDAC treatment.

KLF2 is downregulated in pancreatic ductal adenocarcinoma and inhibits the growth and migration of cancer cells.

Members of the Kruppel-like factor (KLF) family have been considered as the tumor suppressors for their inhibitory effects on cell proliferation. Dysregulation of KLF2, a member of KLF family, has been observed in various cancer types. However, its expression pattern and functions in the pancreatic ductal adenocarcinoma (PDAC) are unknown. In this study, we examined the expression of KLF2 in PDAC clinical samples and evaluated the functions of KLF2 in the progression of PDAC. KLF2 is shown to be downregulated in PDAC clinical samples and overexpression of KLF2 inhibits the growth, migration, and metastasis of PDAC cancer cells. KLF2 interacts with beta-catenin and negatively regulates the beta-catenin/TCF signaling. Taken together, this study suggests the suppressive functions of KLF2 in PDAC.

CIZ1 promoted the growth and migration of gallbladder cancer cells.

Gallbladder cancer (GBC) is one of the most common and aggressive diseases among the gastrointestinal tract malignancies, and the molecular mechanism underlying this disease remains largely unknown. CIZ1 (Cip1 interacting zinc finger protein 1), a binding partner of p21(Cip1/Waf1), has been found to be involved in the tumorigenesis recently. However, the expression pattern and biological functions of CIZ1 in the progression of GBC are not fully understood. In this study, it was found that the expression of CIZ1 was significantly elevated in GBC samples compared to their adjacent normal tissues. Moreover, overexpression of CIZ1 promoted the growth and migration of GBC cells, while knocking down the expression of CIZ1 inhibited the growth, migration, and tumorigenesis of GBC cells in vitro and in vivo. Mechanistically, CIZ1 was found to interact with TCF4 (T-cell factor) and activate beta-catenin/TCF signaling. Our study demonstrated that CIZ1 played an oncogenic role in the progression of GBC and CIZ1 might be a promising target for the treatment of GBC.

Downregulation of RIP140 in hepatocellular carcinoma promoted the growth and migration of the cancer cells.

Hepatocellular carcinoma (HCC) is one of the most common malignancies with a poor response to chemotherapy. It is very important to identify novel diagnosis biomarkers and therapeutic targets. RIP140, a regulator of estrogen receptor, recently has been found to be involved in the tumorigenesis. However, its function in the progression of HCC remains poorly understood. Here, we found that the expression of RIP140 was downregulated in the HCC tissues. Moreover, overexpression of RIP140 in HCC cells inhibited cell proliferation and migration, while downregulation of RIP140 promoted the tumorigenicity of HCC cells in vitro and in vivo. Mechanistically, RIP140 interacted with beta-catenin and negatively regulated beta-catenin/TCF signaling. Taken together, our study suggests the suppressive roles of RIP140 in the pathogenesis of HCC.

Prognostic factors in patients with pancreatic cancer.

The identification of prognostic factors for pancreatic cancer patients could provide insightful information for their management in the clinic. A total of 302 pancreatic cancer patients were enrolled in this study. The clinicopathological characteristics, treatment selection and laboratory test data were retrospectively retrieved from the medical records and follow-up data were obtained via telephone interview. Cox survival analysis was used to assess the potential prognostic factors, and survival curves were obtained by Kaplan-Meier analyses. The mortality rate of the patients was 83.4% (252/302) and the median survival of these patients was 6.1 months, with 1-, 2- and 3-year survival rates of 30.1 (91/302), 10.6 (32/302) and 2.6% (8/302), respectively. The most influential factors for the survival of these patients were the site of primary cancer, tumor stage, treatment selection, serum levels of glutamic-pyruvic transaminase, albumin, lactate dehydrogenase and hemoglobin, and white blood cell counts (P<0.05). The median survival of patients who did not receive any treatment or just received supportive treatment was 1.3 months, while the median overall survival of patients who underwent surgery, chemotherapy, biliary drainage therapy, arterial interventional chemotherapy and comprehensive treatment was 11.0, 7.3, 3.5, 9.0 and 11.0 months, respectively (P<0.05). Furthermore, single-drug chemotherapy was not statistically associated with patient survival in those who received the multi-drug regimen (P>0.05). However, the mortality risk of patients who received platinum chemotherapy was decreased [hazard ratio (HR)=0.56, 95% CI 0.35-0.88, P=0.011] compared to the patients who did not receive this treatment (P<0.05). Tumor stage, treatment selection, serum albumin levels, urea nitrogen, CA19-9, white blood cell and platelet counts were independent prognostic factors for the prediction of survival in pancreatic cancer. Future studies are required in order to verify these data. Chemotherapy with platinum regimens could improve overall survival in patients with pancreatic cancer.

CD4CD25+ regulatory T cells in patients with advanced gastrointestinal cancer treated with chemotherapy.

BACKGROUND: The prevalence of CD4+CD25+ regulatory T cells (Tregs) and other T-cell subsets in gastrointestinal cancer patients treated with chemotherapy was investigated. PATIENTS AND METHODS: The frequencies of Tregs and other T-cell subsets in the peripheral blood of 25 healthy donors and 104 patients with gastrointestinal cancer were measured by flow cytometry. Their plasma cytokine levels were determined by enzyme-linked immunosorbent assay (ELISA). The percentages of the T-cell subsets and their correlation with the outcomes of the gastrointestinal cancer patients after chemotherapy were evaluated. RESULTS: Not only was the prevalence of Tregs in the peripheral blood of gastrointestinal cancer patients significantly higher than that in healthy donors, but it also increased in parallel with tumor progression. Among patients with advanced disease, 3 weeks after chemotherapy, those with higher percentages of Tregs had a poorer prognosis. Interleukin (IL)-2 production showed a reverse trend to Tregs, whereas IL-10 and tumor necrosis factor (TNF)-alpha did not change significantly. CONCLUSIONS: The relative increase in CD4+CD25+ Tregs may be related to immunosuppression and tumor progression in patients with gastrointestinal cancer. Chemotherapy in patients with advanced disease showed that immunosuppression is enhanced early (about 1-2 weeks) after chemotherapy, and increased Tregs 3 weeks after chemotherapy correlated with a poor prognosis.