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Homeostasis of membrane phospholipids plays an important role in cell oncogenesis and cancer progression. The flippase ATPase class I type 8b member 1 (ATP8B1), one of the P4-ATPases, translocates specific phospholipids from the exoplasmic to the cytoplasmic leaflet of membranes. ATP8B1 is critical for maintaining the epithelium membrane stability and polarity. However, the prognostic values of ATP8B1 in colorectal cancer (CRC) patients remain unclear. We analyzed transcriptomics, genomics, and clinical data of CRC samples from The Cancer Genome Atlas (TCGA). ATP8B1 was the only potential biomarker of phospholipid transporters in CRC. Its prognostic value was also validated with the data from the Gene Expression Omnibus (GEO). Compared to the normal group, the expression of ATP8B1 was downregulated in the tumor group and the CRC cell lines, which declined with disease progression. The lower expression level of ATP8B1 was also significantly associated with worse survival outcomes in both the discovery samples (359 patients) and the validation samples (566 patients). In multivariate analyses, low ATP8B1 levels predicted unfavorable OS (adjusted HR 1.512, 95% CI: 1.069-2.137; P = 0.019 ) and were associated with poor progress-free interval (PFI) (adjusted HR: 1.62, 95% CI: 1.207-2.174; P = 0.001 ). The pathway analysis results showed that the underexpression of ATP8B1 was negatively associated with phospholipid transport, phospholipid metabolic process, and cell-cell adherent junction and positively associated with the epithelial-mesenchymal transition in CRC. Our analysis suggests that ATP8B1 is a potential cancer suppressor in CRC patients and may offer new strategies for CRC therapy.

Homeostasis of membrane phospholipids plays an important role in cell oncogenesis and cancer progression. The flippase ATPase class I type 8b member 1 (ATP8B1), one of the P4-ATPases, translocates specific phospholipids from the exoplasmic to the cytoplasmic leaflet of membranes. ATP8B1 is critical for maintaining the epithelium membrane stability and polarity. However, the prognostic values of ATP8B1 in colorectal cancer (CRC) patients remain unclear. We analyzed transcriptomics, genomics, and clinical data of CRC samples from The Cancer Genome Atlas (TCGA). ATP8B1 was the only potential biomarker of phospholipid transporters in CRC. Its prognostic value was also validated with the data from the Gene Expression Omnibus (GEO). Compared to the normal group, the expression of ATP8B1 was downregulated in the tumor group and the CRC cell lines, which declined with disease progression. The lower expression level of ATP8B1 was also significantly associated with worse survival outcomes in both the discovery samples (359 patients) and the validation samples (566 patients). In multivariate analyses, low ATP8B1 levels predicted unfavorable OS (adjusted HR 1.512, 95% CI: 1.069-2.137; P = 0.019) and were associated with poor progress-free interval (PFI) (adjusted HR: 1.62, 95% CI: 1.207-2.174; P = 0.001). The pathway analysis results showed that the underexpression of ATP8B1 was negatively associated with phospholipid transport, phospholipid metabolic process, and cell-cell adherent junction and positively associated with the epithelial-mesenchymal transition in CRC. Our analysis suggests that ATP8B1 is a potential cancer suppressor in CRC patients and may offer new strategies for CRC therapy.

Recent studies indicated that Gene Associated with Retinoid-IFN-Induced Mortality 19 (GRIM-19), a newly discovered mitochondria-related protein, can regulate mitochondrial function and modulate cell viability possibly via interacting with STAT3 signal. In the present study we sought to test: 1) whether GRIM-19 is involved in high glucose (HG) induced altered cell metabolism in both cancer and cardiac cells, 2) whether GRIM-19/STAT3 signaling pathway plays a role in HG induced biological effects, especially whether AMPK activity could be involved. Our data showed that HG enhanced cell proliferation of both HeLa and H9C2 cells, which was closely associated with down-regulated GRIM-19 expression and increased phosphorylated STAT3 level. We showed that GRIM-19 knock-down alone in normal glucose cultured cells can also result in an increase in phosphorylated STAT3 level and enhanced proliferation capability, whereas GRIM-19 over-expression can abolished HG induced STAT3 activation and enhanced cell proliferation. Importantly, both down-regulated or over-expression of GRIM-19 increased lactate production in both HeLa and H9C2 cells. The activated STAT3 was responsible for increased cell proliferation as either AG-490, an inhibitor of JAK2, or siRNA targeting STAT3 can attenuate cell proliferation increased by HG. In addition, HG increased lactate acid levels in HeLa cells, which was also observed when GRIM-19 was genetically manipulated. However, HG did not affect the lactate levels in H9C2 cells. Of note, over-expression of GRIM-19 and silencing of STAT3 both increased lactate production in H9C2 cells. As expected, HG resulted in significant decreases in phosphorylated AMPKα levels in H9C2 cells, but not in HeLa cells. Interestingy, activation of AMPKα by metformin was associated with a reversal of the suppressed GRIM-19 expression in H9C2 cells, the fold of changes in GRIM-19 expression by metformin were much less in HeLa cells. Metformin did not affect the phosphorylated STAT3 lelvels, however, decreased its levels in H9C2, especially in the setting of HG culture. Not like HG alone which resulted in no changes in lactate acid in H9C2 cells, metformin can increase lactate acid levels in H9C2 cells. Increased lactate induced by metformin was also observed in HeLa cells.

Collision cancers are malignancies in the same organ or anatomical site that comprises at least two different tumor components, with no mixed or transitional area between two components. Collision cancers are very rare in the pancreas and periampullary region. The aim of this study was to analyze the clinical and pathological features and prognosis of collision cancer in the pancreas and periampullary region.Patients with collision cancers of the pancreas and periampullary region (n= 10) who had undergone radical surgery were retrospectively studied. Their clinical and pathological features were summarized and the prognostic data were compared with patients with pancreatic adenocarcinomas who underwent radical surgery (n= 87) and with patients with pancreatic or periampullary malignancies who underwent palliative surgery (n= 89).Compared with other cancers at these sites, collision cancer presents no specific clinical features. However, the median survival period of patients with such malignancies was only 10.0 months, which was much less than those with pancreatic adenocarcinomas who underwent radical surgery (27.0 months) and those who received a palliative operation (20.9 months) only.Collision cancers of the pancreas and periampullary region are difficult to diagnose preoperatively. Their prognosis is poor even after radical resection and adjuvant chemotherapy were given.

To investigate the expression of BRSK2 (brain selective kinase 2) in pancreatic ductal adenocarcinoma and to understand its clinical implication.Resected tumor specimens of 79 pancreatic ductal adenocarcinoma were collected and paraffin-embedded for prepare. 0.5 microm sections. Immunohistochemical staining was employed to examine the expression pattern of BRSK2 translated protein. Semi-quantitative analysis was used to evaluate the intensity and content of protein expression in tumor tissues. The expression outcome was compared in peri-tumorous tissues and normal pancreatic tissues. Meanwhile, tumor samples were grouped according to their differentiation, TNM stage, with or without vascular or neural invasion. Then the possible relationship was explored between clinical, pathological and survival data and the expression profile of BRSK2 in tumor tissues.BRSK2's expression was weak in normal pancreatic tissues, including islets and minor ducts such as intercalated ducts, intralobular ducts and interlobular ducts. BRSK2's expression was also weak in peri-tumorous tissues. BRSK2's expression was strong in pancreatic ductal adenocarcinomas. It had a close relationship with lymphatic metastasis, distant metastasis, TNM staging as well as peri-pancreatic neural invasion. Tumors with lymphatic metastasis, distant metastasis and peri-pancreatic neural invasion or at later stages showed a higher expression of BRSK2 than those without or those at early stages. However the expression had no correlation with tumor size, differentiation and vascular invasion. The expression of BRSK2 in pancreatic ductal adenocarcinomas was correlated with the prognosis of patients. Those with a higher expression pattern showed a shorter survival period.BRSK2 is up-regulated in pancreatic ductal adenocarcinoma. And its expression is correlated with tumor biological behaviors and patient prognosis.

OBJECTIVE: Collision cancers are malignancies in the same organ or anatomical site that comprises at least two different tumor components, with no mixed or transitional area between two components. Collision cancers are very rare in the pancreas and periampullary region. The aim of this study was to analyze the clinical and pathological features and prognosis of collision cancer in the pancreas and periampullary region. METHODS: Patients with collision cancers of the pancreas and periampullary region (n= 10) who had undergone radical surgery were retrospectively studied. Their clinical and pathological features were summarized and the prognostic data were compared with patients with pancreatic adenocarcinomas who underwent radical surgery (n= 87) and with patients with pancreatic or periampullary malignancies who underwent palliative surgery (n= 89). RESULTS: Compared with other cancers at these sites, collision cancer presents no specific clinical features. However, the median survival period of patients with such malignancies was only 10.0 months, which was much less than those with pancreatic adenocarcinomas who underwent radical surgery (27.0 months) and those who received a palliative operation (20.9 months) only. CONCLUSION: Collision cancers of the pancreas and periampullary region are difficult to diagnose preoperatively. Their prognosis is poor even after radical resection and adjuvant chemotherapy were given.