Identification of biomarkers related to Tumor-Infiltrating Lymphocytes (TILs) infiltration with gene co-expression network in colorectal cancer.

Colorectal cancer (CRC) is one of the most common tumors, ranking second in the global cause of death from cancer. The prognosis of advanced patients is still very poor. In this study, hub modules with the highest association with tumor-infiltrating immune cells were identified by weighted gene co-expression network analysis based on CRC expression data from the Gene Expression Omnibus database. Next, three hub genes (ADAM8, IL-1A, VAV3) related to infiltrating immune cells were identified by co-expression network and prognostic analysis. After analysis and verification of the TIMER database, ADAM8 was selected as a prognostic biomarker. Finally, the result of functional test showed that ADAM8 gene expression down-regulation partially reversed the immune tolerance of CRC cells to TILs. By bioinformatics analysis methods and the experimental techniques, we identified ADAM8 as a prognostic biomarker and clinical therapeutic target related to tumor-infiltrating immune cells in CRC.

ABO blood type, smoking status, other risk factors and prognosis of pancreatic ductal adenocarcinoma.

The aim of this observational study was to test whether ABO blood type was a prognostic factor for pancreatic ductal adenocarcinoma (PDAC) patients and whether other risk factors could influence pancreatic cancer patients' survival. This study included 610 patients who were diagnosed as pancreatic cancer and had undergone radical surgery. Patients' characteristics included age, gender, tumor stage, tumor grade, adenosquamous carcinoma (ASC) status, preoperative serum carbohydrate antigen 19-9 (CA19-9) levels, preoperative serum carcinoembryonic antigen (CEA) levels, ABO blood type, smoking status, and drinking status were analyzed in this study. Cox proportional hazards regression model and Kaplan-Meier method were used to evaluate the role of prognostic factors. For pancreatic cancer patients undergoing radical surgery, the overall survival was worse for ASC patients than PDAC patients (Log-rank = 11.315, P < .001). Compared with ASC patients (Log-rank < 0.001, P = .996), PDAC patients can benefit from chemotherapy (Log-rank = 17.665, P < .001). For PDAC patients, O blood type had better overall survival than non-O blood type (Log-rank = 4.153, P = .042). Moreover, the group with higher serum levels of CA19-9 had poor prognosis compared to another group with low serum CA19-9 (Log-rank = 4.122, P = .042). Higher CEA levels indicated poor prognosis (Log-rank = 13.618, P < .001). In conclusion, ASC status was associated with overall survival of pancreatic cancer patients and cannot benefit from postoperative chemotherapy. Non-O blood type was a prognostic factor for PDAC patients.

Evaluation of the target genes of arsenic trioxide in pancreatic cancer by bioinformatics analysis.

The aim of the present study was to evaluate the potential network of arsenic trioxide (ATO) target genes in pancreatic cancer. The DrugBank, STITCH, cBioPortal, Kaplan-Meier plotter and Oncomine websites were used to analyze the association of ATO and its target genes with pancreatic cancer. Initially, 19 ATO target genes were identified, along with their associated protein-protein interaction networks and Kyoto Encyclopedia of Genes and Genomes pathways. ATO was found to be associated with multiple types of cancer, and the most common solid cancer was pancreatic cancer. A total of 6 ATO target genes (namely AKT1, CCND1, CDKN2A, IKBKB, MAPK1 and MAPK3) were found to be associated with pancreatic cancer. Next, the mutation information of the 6 ATO target genes in pancreatic cancer was collected. A total of 20 ATO interacting genes were identified, which were mainly involved in hepatitis B, prostate cancer, pathways in cancer, glioma and chronic myeloid leukemia. Finally, the genes CCND1 and MAPK1 were detected to be prognostic factors in patients with pancreatic cancer. In conclusion, bioinformatics analysis may help elucidate the molecular mechanisms underlying the involvement of ATO in pancreatic cancer, enabling more effective treatment of this disease.

High levels of serum glypican-1 indicate poor prognosis in pancreatic ductal adenocarcinoma.

Carbohydrate antigen 19-9 (CA19-9) fails to demonstrate the predictive value for early detection pancreatic ductal adenocarcinoma (PDAC). Glypican-1 (GPC1+) exosomes may serve as a noninvasive diagnostic tool to detect early stages of PDAC. Therefore, it is necessary to explore the serum GPC1 levels and determine whether serum GPC1 serves as a novel biomarker for PDAC patients. Blood samples were collected from 156 patients with PDAC, 199 non-cancer controls, and 240 patients with other cancers. Serological levels of GPC1 were examined by enzyme-linked immunosorbent assay (ELISA). Finally, a 5-year follow-up was monitored to evaluate the correlation between serum GPC1 levels and overall survival in 156 patients with PDAC. The results suggested that levels of serum GPC1 and CA19-9 were higher in PDAC patients than that of controls (P < 0.05). Serum GPC1 levels in PDAC were different from those in gallbladder carcinoma (P < 0.001), colorectal carcinoma (P < 0.001), gastric carcinoma (P < 0.001), and prostate cancer (P < 0.001), but not hepatocellular carcinoma (P = 0.395) and cholangiocarcinoma (P = 0.724). Receiver operating characteristic curve (ROC) analysis showed that serum CA19-9 was significantly better than serum GPC1 in distinguishing PDAC patients from the controls (AUC, 95% CI: 0.908, 0.868-0.947 vs 0.795, 0.749-0.841, respectively). The serum GPC1 cannot be used as a serum diagnostic biomarker for PDAC patients. The level of serum GPC1 decreased 2 days after surgery (P = 0.001), which were not different from serum GPC1 levels in healthy control (P = 0.381). The overall survival rate was shorter in patients with high levels of serum GPC1 compared to those with low levels of serum GPC1 (log-rank = 5.16, P = 0.023). Taken together, the results indicate that high levels of serum GPC1 predict poor prognosis in PDAC patients. Serum GPC1 may be a prognosis factor for PDAC patients.

Autoantibodies against glucose-regulated protein 78 as serological biomarkers in metastatic and recurrent hepatocellular carcinoma.

PURPOSE: To identify Heptocellular carcinoma (HCC) associated antigens by proteomics, and validate whether autoantibodies against tumor-associated antigens (TAAs) could be used for diagnosis and conditional monitoring. RESULTS: The 78 kDa glucose regulated protein (GRP78) was selected as a candidate TAA. The titers of autoantibodies against 78 kDa glucose regulated protein (GRP78) from patients with HCC, liver cirrhosis (LC), and chronic hepatitis (CH) were significantly higher than that from normal controls (P<0.05, P<0.001, and P<0.01, respectively). The expression of autoantibodies against GRP78 was associated with clinical stage (P<0.01), portal vein invasion (P<0.05), and metastasis (P<0.05). The expression of anti-GRP78 antibodies was significantly higher 1 month after surgery in recurrent patients who had accepted hepatic resection 1 month after surgery compared to patients who had surgery before surgery or within 1 week after surgery (P<0.01 and P<0.001). Immunohistochemistry (IHC) showed higher expression of GRP78 in HCC compared to the non-HCC liver tissues (P <0.05). MATERIALS AND METHODS: HCC serum with high titer of autoantibodies against TAAs were screened and used for a proteome-based approach to identify HCC associated antigens. Indirect enzyme-linked immunoassay (ELISA) was used to detect the corresponding autoantibodies against TAAs. CONCLUSION: GRP78 is an autoantigen that could stimulate autoimmune responses and serve as a potential marker for recurrent and metastatic progression in HCC.

Serum dickkopf-1 is a novel serological biomarker for the diagnosis and prognosis of pancreatic cancer.

PURPOSE: To identify whether Dickkopf-1 (DKK1) could be a potential biomarker for early detection and prognosis in patients with pancreatic cancer (PC). METHODS: Serum was collected from 140 patients with pancreatic adenocarcinoma and 92 control patients without pancreatic adenocarcinoma. Serological levels of DKK1 were examined by enzyme-linked immunosorbent assay (ELISA). The sensitivity and specificity was compared with carbohydrate antigen 19-9 (CA19-9). A 2-year follow-up was monitored to evaluate the correlation between DKK1 serum levels and overall survival. The expression of DKK1 in PC tumor tissues was also evaluated using immunohistochemistry staining. RESULTS: Serum levels of DKK1 and CA19-9 were elevated in PC patients in the early-stage cases. These levels increased with the advancement of clinical stage. There was significant difference in DKK1 serum levels between early and advanced PC stages. Receiver operating characteristic curve (ROCC) analysis showed that DKK1 was significantly better than CA19-9 in differentiating patients with PC from the controls (area under the curve (AUC) 0.919 versus 0.853, respectively), especially in distinguishing early-stage cancer from chronic pancreatitis (CP). The expression of DKK1 in PC tissues correlated with its expression in serum samples. The overall survival rate was 24.4% in the group with higher DKK1 levels and was found to be significantly different from the group with lower DKK1 levels (33.3%). CONCLUSION: DKK1 may be a novel diagnostic/prognostic biomarker for PC.

Autoimmune response to PARP and BRCA1/BRCA2 in cancer.

PURPOSE: To determine the role of autoantibodies to PARP1 and BRCA1/BRCA2 which were involved in the synthetic lethal interaction in cancer. METHODS: Enzyme-Linked Immunosorbent Assay (ELISA) was used to detect autoantibodies to PARP1 and BRCA1/BRCA2 in 618 serum samples including 131 from breast cancer, 94 from lung cancer, 34 from ovarian cancer, 107 from prostate cancer, 76 from liver cancer, 41 from pancreatic cancer and 135 from normal individuals. The positive sera with ELISA were confirmed by Western blot. Immunohistochemistry was used to examine the expression of PARP1 and BRCA1/BRCA2 in breast cancer. RESULTS: Autoantibody frequency to PARP1, BRCA1, and BRCA2 in cancer varied from 0% to 50%. When the sera from cancer patients were tested for the presence of autoantibodies to PARP1 and BRCA1/BRCA2, the autoantibody responses slightly decreased and the positive autoantibody reactions varied from 0% to 50.0%. This was significantly higher autoantibody responses to PARP1 and BRCA1/BRCA2 (especially to PARP1 and BRCA1) in ovarian cancer and breast cancer compared to normal control sera (P < 0.001 and P < 0.01). Immunohistochemistry indicated that Pathology Grade at diagnosis to PARP1 expression in breast cancer was different (P < 0.05). CONCLUSIONS: Different cancers have different profiles of autoantibodies. The autoantibodies to proteins involving the synthetic lethal interactions would be novel serological biomarker in some selective cancers.

MiR-21 promotes intrahepatic cholangiocarcinoma proliferation and growth in vitro and in vivo by targeting PTPN14 and PTEN.

Intrahepatic cholangiocarcinoma (ICC) constitutes the second-most common primary hepatic malignancy. MicroRNAs (miRNAs) play important roles in the pathogenesis of ICC. However, the clinical significance of miR-21 levels in ICC remains unclear. Here, we investigated the role of miR-21 in ICC and found that its expression was significantly upregulated in serum of ICC patients. Serum miR-21 levels robustly distinguished ICC patients from control subjects. Further experiments showed that inhibition of miR-21 suppressed ICC cell proliferation in vitro and tumor growth in vivo. Specifically, inhibition of miR-21 induced cell cycle arrest and apoptosis. Moreover, PTPN14 and PTEN were identified as direct and functional targets of miR-21. Finally, we showed high expression levels of miR-21 were closely related to adverse clinical features, diminished survival, and poor prognosis in ICC patients. This study revealed functional and mechanistic links between miR-21 and tumor suppressor genes, PTPN14 and PTEN, in the pathogenesis of ICC. MiR-21 not only plays important roles in the regulation of cell proliferation and tumor growth in ICC, but is also a diagnostic and prognostic marker, and a potential therapeutic target for ICC.