This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractResistance to chemotherapy is a major challenge for the treatment of patients with colorectal cancer (CRC). Previous studies have found that microRNAs (miRNAs) play key roles in drug resistance; however, the role of miRNA-373-3p (miR-375-3p) in CRC remains unclear. The current study aimed to explore the potential function of miR-375-3p in 5-fluorouracil (5-FU) resistance. MicroRNA-375-3p was found to be widely downregulated in human CRC cell lines and tissues and to promote the sensitivity of CRC cells to 5-FU by inducing colon cancer cell apoptosis and cycle arrest and by inhibiting cell growth, migration, and invasion in vitro. Thymidylate synthase (TYMS) was found to be a direct target of miR-375-3p, and TYMS knockdown exerted similar effects as miR-375-3p overexpression on the CRC cellular response to 5-FU. Lipidcoated calcium carbonate nanoparticles (NPs) were designed to cotransport 5-FU and miR-375-3p into cells efficiently and rapidly and to release the drugs in a weakly acidic tumor microenvironment. The therapeutic effect of combined miR-375 + 5-FU/NPs was significantly higher than that of the individual treatments in mouse s.c. xenografts derived from HCT116 cells. Our results suggest that restoring miR-375-3p levels could be a future novel therapeutic strategy to enhance chemosensitivity to 5-FU. K E Y W O R D S5-fluorouracil, chemosensitivity, colorectal cancer, miR-375-3p, nanoparticles | INTRODUC TI ONAlthough considerable progress has been made in the treatment of CRC in recent years, CRC accounts for approximately 13% of all tumors and is the second leading cause of tumor-related death in developed countries. 1-3 Fluorouracil-based chemotherapy has served as the first-line standard of care and most common regimen for CRC over the past 50 years. 4,5 However, patient resistance to 5-FU is a major obstacle to effective therapy. Therefore, efforts to clarify the molecular mechanism underlying 5-FU resistance and to identify new

Colorectal cancer (CRC) is the second most lethal malignancy around the world. Limited efficacy of immunotherapy creates an urgent need for development of novel treatment targets. Secretogranin II (SCG2) is a member of the chromogranin family of acidic secretory proteins, has a role in tumor microenvironment (TME) of lung adenocarcinoma and bladder cancer. Besides, SCG2 is a stroma-related gene in CRC, its potential function in regulating tumor immune infiltration of CRC needs to be fully elucidated. In this study, we used western blot, real-time PCR, immunofluorescence and public databases to evaluate SCG2 expression levels and distribution. Survival analysis and functional enrichment analysis were performed. We examined TME and tumor infiltrating immune cells using ESTIMATE and CIBERSORT algorithm. The results showed that SCG2 expression was significantly decreased in CRC tumor tissues, and differentially distributed between tumor and adjacent normal tissues. SCG2 was an independent prognostic predictor in CRC. High expression of SCG2 correlated with poor survival and advanced clinical stage in CRC patients. SCG2 might regulate multiple tumor- and immune-related pathways in CRC, influence tumor immunity by regulating infiltration of immune cells and macrophage polarization in CRC.

Colorectal cancer (CRC) is one of the most common carcinomas and the fourth leading cause of cancer-related death worldwide. One of the obstacles in the successful treatment of CRC is a high rate of recurrence. We aimed to construct weighted gene co-expression network analysis (WGCNA) to identify key modules and hub genes in association with recurrence in CRC patients. We firstly used the microarray data, GSE41258, to construct a co-expression network and identify gene modules. Furthermore, protein and protein interaction (PPI) network was also performed to screen hub genes. To validate the hub genes, an independent dataset GSE17536 was used for survival analyses. Additionally, another two databases were also performed to investigate the survival rates and expression levels of hub genes. Gene set enrichment analyses (GSEA) combined with gene ontology (GO) were performed to further explore function and mechanisms. In our study, the midnightblue module was identified to be significant, 15 hub genes were screened, four of which were identified as hub nodes in the PPI network. In the test dataset, we found higher expression of MYL9 and CNN1 were significantly associated with shorter survival time of CRC patients. GO analyses showed that MYL9 and CNN1 were enriched in "muscle system process" and "cytoskeletal protein binding". GSEA found the two hub genes were enriched in "pathways in cancer" and "calcium signaling pathway". In conclusion, our study demonstrated that MYL9 and CNN1 were hub genes associated with the recurrence of CRC, which may contribute to the improvement of recurrence-free survival time of CRC patients.