One major reason for the failure of advanced colorectal cancer (CRC) treatment is the occurrence of chemoresistance to fluoropyrimidine (Fu)-based chemotherapy. Accumulating evidence indicates that long non-coding RNAs (lncRNAs) play a critical role in cancerous processes as either oncogenes or tumor suppressor genes. Here, we observed lncRNA TUG1 was associated to the 5-Fu resistance in colorectal cancer. Firstly, quantitative analysis indicated that TUG1 was significantly increased in recurrence CRC patient samples. Kaplan-Meier survival analysis indicated that high TUG1 expression in CRC tissues was significantly associated with a higher rate of disease progression. TUG1 knockdown re-sensitized the 5-Fu resistance in colorectal cancer cells, which were 5-Fu-resistant colorectal cell line. Furthermore, bioinformatics analysis showed that miR-197-3p could directly bind to TUG1 suggesting TUG1 might work as a ceRNA to sponge miR-197-3p. Extensively, our study also showed that TYMS was the direct target of miR-197-3p in CRC cells. Taken together, our study suggests that TUG1 mediates 5-Fu resistance in CRC via miR-197-3p/TYMS axis.

Hypoxia is serving crucial roles in cancers. This study aims to comprehensively analyze the molecular features and clinical relevance of a well-defined hypoxia-associated signature in pan-cancer using multi-omics data. Data were acquired from TCGA, CCLE, GDSC, and GEO. RNA expression pattern, copy number variation (CNV), methylation, and mutation of the signature were analyzed. The majority of the 15 genes were upregulated in cancer tissues compared with normal tissue, and RNA expression was negatively associated with methylation level. CNV occurred in almost all the cancers, whereas mutation frequency was low across different cancer types. The signature was also closely related to cancer hallmarks and cancer-related metabolism pathways. NDRG1 was upregulated in kidney cancer tissues as indicated by immunohistochemistry. Besides, most of the 15 genes were risk factors for patients' overall survival. Our results provide a valuable resource that will guide both mechanistic and therapeutic analyses of the hypoxia signature in cancers.

Background: Although the recommended minimal examined lymph node (ELN) number in rectal cancer (RC) is 12, this standard remains controversial because of insufficient evidence. We aimed to refine this definition by quantifying the relationship between ELN number, stage migration and long-term survival in RC. Methods: Data from a Chinese multi-institutional registry (2009-2018) and the Surveillance, Epidemiology, and End Results (SEER) database (2008-2017) on stages I–III resected RC were analysed to determine the relationship between ELN count, stage migration, and overall survival (OS) using multivariable models. The series of odds ratios (ORs) for negative-to-positive node stage migration and hazard ratios (HRs) for survival with more ELNs were fitted using a Locally Weighted Scatterplot Smoothing (LOWESS) smoother, and structural breakpoints were determined using the Chow test. The relationship between ELN and survival was evaluated on a continuous scale using restricted cubic splines (RCS). Results: The distribution of ELN count between the Chinese registry (n=7694) and SEER database (n=21 332) was similar. With increasing ELN count, both cohorts exhibited significant proportional increases from node-negative to node-positive disease (SEER, OR, 1.012, P<0.001; Chinese registry, OR, 1.016, P=0.014) and serial improvements in OS (SEER: HR, 0.982; Chinese registry: HR, 0.975; both P<0.001) after controlling for confounders. Cut-point analysis showed an optimal threshold ELN count of 15, which was validated in the two cohorts, with the ability to properly discriminate probabilities of survival. Conclusions: A higher ELN count is associated with more precise nodal staging and better survival. Our results robustly conclude that 15 ELNs are the optimal cut-off point for evaluating the quality of lymph node examination and stratification of prognosis.

MicroRNAs (miRNAs) are deregulated in a number of cancers including colorectal cancer. MiR-30c belongs to miR-30 family, and is involved in a variety of malignant diseases. In this study, we detected the expression of miR-30c in colon cancer cell lines and clinical colon cancer specimens. MiR-30c was shown to be dramatically down-regulated both in cell lines and cancer tissues. Additionally, miR-30c could inhibit cancer cell growth, migration and invasion in vitro. Consistently, stable over-expression of miR-30c inhibited the growth and lung metastasis of colon cancer cell xenografts in vivo. Furthermore, bioinformatics algorithm and luciferase reporter assay indicated ADAM19 as a direct target of miR-30c. Of interest, further experiments demonstrated that inhibition of ADAM19 by miR-30c partially mediated the anti-tumor effect of miR-30c. Overall, our study provides the new insight that miR-30c inhibited colon cancer cells via targeting ADAM19. Thus, miR-30c might serve as a promising therapeutic strategy for colon cancer treatment.

Fibroblast activation protein alpha (FAP) is a marker of cancer-associated fibroblast, which is also expressed in cancer epithelial cells. However, the role of FAP in colorectal cancer (CRC) cells remains to be elucidated. Here we investigate the expression pattern of FAP in CRC tissues and cells to prove that FAP is upregulated in CRC cells. Loss- of and gain-of-function assays identified FAP promotes migration and invasion instead of an effect on cell proliferation. Microarray assays are adopted to identify the different expressed genes after FAP knockdown and gene set enrichment analysis (GSEA) is used to exploit the involved signaling pathway. Our works reveal FAP exerts a function dependent on NF-κB signaling pathway and FAP expression is associated with NF-κB signaling pathway in clinical samples. Our work shows FAP is secreted by CRC cells and soluble FAP could promote metastasis. To investigate the mechanism of FAP influencing the NF-κB signaling pathway, LC/MS is performed to identify the proteins interacting with FAP. We find that FAP binds to ENO1 and activates NF-κB signaling pathway dependent on ENO1. Blocking ENO1 could partially reverse the pro-metastatic effect mediated by FAP. We also provide evidences that both FAP and ENO1 are associated with CRC stages, and high levels of FAP and ENO1 predict a poor survival in CRC patients. In summary, our work could provide a novel mechanism of FAP in CRC cells and a potential strategy for treatment of metastatic CRC.

Although the occurrence of tumour deposits (TDs) without metastatic lymph nodes (mLNs) is classified as “N1c” in the 8^th TNM staging system for colorectal cancer (CRC), the prognostic significance of the TD count is still controversial. A total of 39155 CRC patients were collected from the Surveillance, Epidemiology, and End Results (SEER) database. The potential associations between baseline characteristics and TD status were evaluated using the χ² test. Cancer-specific survival (CSS) rates were calculated by using the Kaplan-Meier method, and CSS comparisons were performed by using the log-rank test. The results showed that TD count was an important prognostic factor and that the number of TDs was negatively correlated with the prognosis of CRC patients. We found that the prognostic value of one TD is equivalent to that of two mLNs based on the comparison of CSS rates. Accordingly, we proposed a novel N staging system by integrating the TD count into the N category with the ratio of TDs to mLNs being 1:2. There were no prognostic differences in patients with or without TDs in each novel N category. Weighing one TD as two mLNs in this novel TNM staging system is superior to the “N1c” classification in the 8^th TNM staging system in evaluating the prognosis of CRC patients.