Search

BackgroundPatients with stage I-III gastric cancer (GC) undergoing R0 radical resection display extremely different prognoses. How to discriminate high-risk patients with poor survival conveniently is a clinical conundrum to be solved urgently.MethodsPatients with stage I-III GC from 2010 to 2016 were included in our study. The associations of clinicopathological features with disease-free survival (DFS) and overall survival (OS) were examined via Cox proportional hazard model. Nomograms were developed which systematically integrated prognosis-related features. Kaplan–Meier survival analysis was performed to compare DFS and OS among groups. The results were then externally validated by The Sixth Affiliated Hospital, Sun Yat-sen University.ResultsA total of 585 and 410 patients were included in the discovery cohort and the validation cohort, respectively. T stage, N stage, lymphatic/vascular/nerve infiltration, preoperative CEA, and CA19-9 were independent prognostic factors (P < 0.05). Two prognostic signatures with a concordance index (C-index) of 0.7502 for DFS and 0.7341 for OS were developed based on the nomograms. The 3-year and 5-year calibration curves showed a perfect correlation between predicted and observed outcomes. Patients were divided into three risk groups (low, intermediate, high), and distinct differences were noticed (p < 0.001). Similar results were achieved in the validation cohort. Notably, a free website was constructed based on our signatures to predict the recurrence risk and survival time of patients with stage I-III GC.ConclusionsThe signatures demonstrate the powerful ability to conveniently identify distinct subpopulations, which may provide significant suggestions for individual follow-up and adjuvant therapy.

BackgroundPancreatic adenocarcinoma (PAAD) is a treatment-refractory cancer with poor prognosis. Accumulating evidence suggests that squalene epoxidase (SQLE) plays a pivotal role in the development and progression of several cancer types in humans. However, the function and underlying mechanism of SQLE in PAAD remain unclear.MethodsSQLE expression data were downloaded from The Cancer Genome Atlas and the Genotype-Tissue Expression database. SQLE alterations were demonstrated based on the cBioPortal database. The upstream miRNAs regulating SQLE expression were predicted using starBase. The function of miRNA was validated by Western blotting and cell proliferation assay. The relationship between SQLE expression and biomarkers of the tumor immune microenvironment (TME) was analyzed using the TIMER and TISIDB databases. The correlation between SQLE and immunotherapy outcomes was assessed using Tumor Immune Dysfunction and Exclusion. The log-rank test was performed to compare prognosis between the high and low SQLE groups.ResultsWe demonstrated a potential oncogenic role of SQLE. SQLE expression was upregulated in PAAD, and it predicted poor disease-free survival (DFS) and overall survival (OS) in patients with PAAD. “Amplification” was the dominant type of SQLE alteration. In addition, this alteration was closely associated with the OS, disease-specific survival, DFS, and progression-free survival of patients with PAAD. Subsequently, hsa-miR-363-3p was recognized as a critical microRNA regulating SQLE expression and thereby influencing PAAD patient outcome. In vitro experiments suggested that miR-363-3p could knock down the expression of SQLE and inhibit the proliferation of PANC-1. SQLE was significantly associated with tumor immune cell infiltration, immune checkpoints (including PD-1 and CTLA-4), and biomarkers of the TME. KEGG and GO analyses indicated that cholesterol metabolism-associated RNA functions are implicated in the mechanisms of SQLE. SQLE was inversely associated with cytotoxic lymphocytes and predicted immunotherapy outcomes.ConclusionsCollectively, our results indicate that cholesterol metabolism-related overexpression of SQLE is strongly correlated with tumor immune infiltration and immunotherapy outcomes in patients with PAAD.

Background: Various clinical and pathological indicators affect the prognosis of stage II and III colorectal cancer (CRC). Nevertheless, few studies have systematically integrated these indicators to construct a signature for assessing the prognostic risk.Methods: Patients with stage II-III CRC underwent R0 radical resection from 2009 to 2016 were included in this study. All clinical and follow-up data were collected. Our study mainly incorporated an internal training cohort and an external validation cohort from two centers. Data processing and data analysis were performed in the R language. Cox proportional hazard regression was used for univariate and multivariable analyses. The log-rank test was performed to compare prognosis among groups.Results: A total of 1200 eligible patients were included in our study. 8 variables, including T/N stage, lymphatic/vascular infiltration, preoperative CEA, CA125 and CA199, were included and the nomogram was established in the signature for predicting OS. The concordance index of the signature was 0.72. The 3-year and 5-year calibration curves of CRC based on the nomogram showed perfect correlation between predicted and observed outcomes. Obvious differences were observed in the survival of different risk groups (p < 0.001). Patients with low risk score signature had a 5-year OS rate of 77%, whereas patients with high risk score signature had the worst 5-year OS rate (only 8%). Furthermore, our signature also achieved similar performance in external cohort validation.Conclusions: The signature based on clinical and pathologic factors had favorable accuracy for predicting the prognosis of CRC. Therefore, our signature may provide significant suggestions for clinical work, particularly in identifying high-risk stage II and III CRC.

Background: Preoperative serum tumor markers have been widely used to predict prognosis in stage II and III colorectal cancer (CRC). However, few previous studies addressed the effect of increased preoperative numbers of tumor markers. Methods: Patients with stage II and III CRC who underwent curative resection were included from January 2009 to October 2015. The relationship between serum tumor markers and clinicopathological parameters was analyzed. DFS and OS were compared in stage II and III CRC. Results: The median follow-up was 45 months. In this study, 735 enrolled patients were assessed based on the numbers of increased tumor markers. We found that these increased tumor markers were closely associated with clinical stage, T stage, N stage, tumor location, pathology type, differentiation, lymphatic invasion and vascular invasion (all p values < 0.05). Furthermore, the number of increased tumor markers directly affected the survival of patients with CRC after curative surgery. The 3-year DFS and OS of patients with a score of 0 were 84.0% and 91.0%, respectively, which are much higher than those of patients with a score of 4 (42.9% and 37.8%, respectively) (p < 0.05). The 5-year DFS and OS of patients with a score of 0 were 75.9% and 77.9%, respectively, which are much higher than those of patients with a score of 4 (31.7% and 23.6%, respectively). Interestingly, our results suggested that stage III CRC patients with a score of 0 had longer DFS and OS times than stage II patients with scores of 3 and 4. Further analysis revealed statistically significant differences in OS (p < 0.05) but not in DFS. Conclusions: The number of increased tumor markers could significantly predict prognosis in stage II and III CRC. In addition, these increased tumor markers had direct impacts on metastasis as well as the recurrence status and survival time of stage II and III CRC patients.

SLC39A7 (zip7) is a zinc transporter that plays a key role in intestinal epithelial self-renewal. However, little is known about SLC39A7 in colorectal cancer. To assess the biological function of SLC39A7 in colorectal cancer, the expression of SLC39A7 in human colorectal tumors and five colorectal cancer cell lines were evaluated by Oncomine Cancer Microarray Database and western blot analysis. In addition, short hairpin RNAs specifically targeting SLC39A7 were transfected into HCT116 and SW1116 cells to knockdown SLC39A7 expression. Then, the effects of SLC39A7 knockdown on colorectal cancer cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide, colony-forming assay and flow cytometry. Our results showed that colorectal tumors have higher expression levels of SLC39A7 than normal colon tissues. Knockdown of SLC39A7 exhibited a significant decrease in cell viability and proliferation of colorectal cancer cells. It was also shown that knockdown of SLC39A7 interfered with cell cycle progression and induced G2/M cell cycle arrest, as well as boosted early and late apoptosis in colorectal cancer cells. Furthermore, downregulation of SLC39A7 promoted the cleavage of PARP and enhanced the expression of Bad, Caspase-9, and cleaved-Caspase-3, as well as suppressed Bcl-2 expression. In conclusion, our results suggest that SLC39A7 plays a crucial role in the proliferation and survival of colorectal cancer cells, which associates with colorectal tumorigenesis.

MicroRNA‐145 (miR‐145), as a tumor‐suppressive miRNA, has been demonstrated down‐regulated in colorectal cancer (CRC) cells, and could inhibit CRC cells growth. However, the molecular pathway in which miR‐145 modulates CRC malignant transformation has not been fully revealed. Here, we reported an intense correlation between the expressions of PAK4 and miR‐145 in human CRC cell lines. Transwell assay verified overexpression of miR‐145, as well as knockdown of PAK4, significantly suppressed cell migration and invasion ability. The impaired migration and invasion ability of SW1116 cells was affected through the down‐regulation of phosphorylation level of LIMK1 and cofilin in a PAK4‐dependent manner. Collectively, we have demonstrated that miR‐145 suppressed CRC migration and invasion through PAK4 pathway, which provides an attractive microRNA‐based therapeutic target for CRC.

Colorectal cancer (CRC) is one of the most common neoplasms worldwide. However, the mechanisms underlying its development are still poorly understood. Thyroid hormone Receptor Interactor 13 (TRIP13) is a key mitosis regulator, and recent evidence has shown that it is an oncogene. Here, we report that TRIP13, which is overexpressed in CRC, is correlated with the CEA (carcino-embryonic antigen), CA19-9 (carbohydrate antigen 19-9) and pTNM (pathologic primary tumor, lymph nodes, distant metastasis) classification. Multivariate analyses showed that TRIP13 might serve as an independent prognostic marker of CRC. We also found that TRIP13 promoted CRC cell proliferation, invasion and migration in vitro and subcutaneous tumor formation in vivo. Furthermore, the potential mechanism underlying these effects involves the interaction of TRIP13 with a 14-3-3 protein, YWHAZ, which mediates G2-M transition and epithelial-mesenchymal transition (EMT). Together, these findings suggest that TRIP13 may be a potential biomarker and therapeutic target for CRC.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, with the mortality increasing steadily over the last decade. Myosin VI (MYO6) expression is found to be elevated in some types of human carcinoma cell types, suggesting that it may be a sensitive biomarker for the diagnosis and follow-up. In this study, we first used the Oncomine database to explore the expression of MYO6 in CRC tissues, and then constructed a plasmid of RNA interference targeting MYO6 gene. After transfection of lentivirus targeting MYO6 into SW1116 cells, cell viability and proliferation were measured with 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assay. Cell cycle distribution was assayed by flow cytometry and apoptosis was evaluated by Annexin V. MYO6 expression was detected by quantitative real-time polymerase chain reaction and western blot analysis. It was found that MYO6 mRNA was upregulated in CRC tissues using data mining of public Oncomine microarray datasets. Depletion of MYO6 significantly inhibited cell proliferation and colony formation. In addition, knockdown of MYO6 slightly arrested cell cycle in G0/G1 phase, but remarkably increased the proportion of the sub-G1 phase of cell with the increase of apoptotic cells. These results suggest that MYO6 may promote cell growth and may be used as a potential target for anticancer therapy of CRC.