Long non-coding FAM201A accelerates the tumorigenesis and progression of colorectal cancer through miR-3163/MACC1 axis.

Colorectal cancer (CRC) is the leading contributor to cancer-relevant deaths worldwide with severe incidence and mortality. An extensive body of evidence has demonstrated that lncRNA plays a critical role in the oncogenicity of CRC. Despite the oncogenic function of FAM201A in esophageal squamous cell cancer and non-small-cell lung cancer, the potential of FAM201A in CRC progression remains unknown. FAM201A expression level was significantly enhanced in CRC cells compared with normal cells. Further, functional experiments illustrated that knockdown of FAM201A restrained cell growth, stemness and promoted chemoresistance of CRC cells. By exploring molecular mechanism of FAM201A, we found that FAM201A acted as a sponge of miR-3163. More importantly, oncogene MACC1 was confirmed to be a direct target of miR-3163 and FAM201A modulated MACC1 expression level via competing for miR-3163. Subsequently, we testified that FAM201A exerted its role in the tumorigenesis and development of CRC through targeting miR-3163/MACC1. Animal assay certified that FAM201A expedited CRC cell growth in vivo. In conclusion, our study was the first to unveil that FAM201A promoted cell proliferation and CSC characteristics in CRC via regulation of the miR-3163/MACC1 axis, which provided clues for the clinical treatment of patients with this disease.

Low-sample-consumption and ultrasensitive detection of procalcitonin by boronate affinity recognition-enhanced dynamic light scattering biosensor.

Accurate determination of procalcitonin (PCT) is highly crucial in bacterial infection diagnosis. Many biosensors previously developed suffer from large sample consumption or lengthy waiting time, which raise difficulties for more vulnerable patients, such as infants, old people, and other critically ill patients. To address this dilemma, we present an innovative boronate affinity recognition (BAR)-enhanced dynamic light scattering (DLS) biosensor to achieve ultrasensitive PCT detection. In this biosensing system, monoclonal antibody-modified magnetic nanoparticles (MNP@mAb) are designed as probes to capture PCT from serum samples and generate DLS signal transduction. Polyvalent phenylboronic acid-labeled bovine serum albumin (BSA@PBA) is used as scaffold to aggregate MNP@mAb and PCT (MNP@mAb-PCT) complex because of the specific interaction of cis-diol-containing PCT with boronic acid ligands on the surface of BSA@PBA. The BAR-enhanced DLS biosensor shows ultrahigh sensitivity to PCT determination due to high binding affinity, with the limit of detection of 0.03 pg/mL. The total detection time of PCT in whole blood or serum is less than 15 min with small sample consumption (about 1 µL) due to the rapid magnetic separation and aggregation of MNP@mAb-PCT triggered by BSA@PBA. In addition, the proposed DLS biosensor exhibits a high specificity for PCT quantitative detection. Therefore, this work provides a promising and versatile strategy for extending DLS biosensor to rapid and ultrasensitive detection of trace PCT for broader patients and more urgent cases.

CD38 deficiency up-regulated IL-1ß and MCP-1 through TLR4/ERK/NF-κB pathway in sepsis pulmonary injury.

As a disease with high mortality, many cytokines and signaling pathways are associated with sepsis. The pro-inflammatory cytokines and chemokines are participating in the pathogenesis of sepsis, especially in early stage. Moreover, the releases and expressions of cytokines are regulated by numerous signaling pathways, including TLR4/ERK pathway. But despite many studies have expounded the pathogenesis of sepsis and the regulation of cytokines in sepsis, how CD38 influence the expressions of related molecules in sepsis are still unknown. The aim of this study is illuminating the alteration of cytokines and signaling pathways in CD38-/- mice injected with Escherichia coli. Compared with WT mice, E. coli infection results in more severe pulmonary injuries and higher mRNA expressions of cytokines. Compared with E. coli infected WT mice, CD38 knockout leads to aggravated pulmonary injury, increased phosphorylated ERK1/2, p38 and NF-κB p65, and enhanced levels of IL-1ß, iNOS and MCP-1. While compared with E. coli infected CD38-/- mice, TLR4 mutation results in alleviated pulmonary injury, down-regulated phosphorylated ERK1/2 and NF-κB p65, and decreased expressions of IL-1ß and MCP-1. CD38 deficiency increased the expressions of IL-1ß andMCP-1 and aggravated pulmonary injury through TLR4/ERK/NF-κB pathway in sepsis.

TLR4-NLRP3-GSDMD-Mediated Pyroptosis Plays an Important Role in Aggravated Liver Injury of CD38-/- Sepsis Mice.

Clinically, severe bacterial infection can cause septicemia and multiple organ dysfunction syndrome, especially liver injury. CD38 is closely related to many inflammatory pathways, but its role in liver injury caused by bacterial infection remains unclear. The purpose of this study is to discuss the specific role of CD38 in bacterial liver injury. Eight-week-old male C57BL/6 mice (WT, CD38-/- and CD38-/-TLR4mut) were used and stimulated with Escherichia coli (ATCC25922) or PBS, intraperitoneally. After 3 hours of bacterial stimulation, serum was collected to detect ALT and AST concentration, and liver tissue was harvested for hematoxylin and eosin staining and bacterial culture. The mRNA expressions of TLR4, NLRP3, IL-1ß, IL-18, and GSDMD were quantitatively determined by RT-qPCR. The expressions of TLR4, MyD88, TRIF, NF-κB p65, NLRP3, GSDMD, and cytokines were detected by Western blot. The expression and localization of ERK1/2 were detected by immunohistochemistry and Western blot. The results showed that bacterial stimulation could upregulate the expression of inflammatory cytokines, leading to hepatic dysfunction. Moreover, bacterial stimulation of CD38-deficient mice can aggravate the inflammatory response, the expressions of TLR4, NF-κB, and ERK1/2 were significantly increased, and the biomarkers related to pyroptosis also manifested more obvious pyroptosis. However, TLR4 mutation significantly alleviated inflammation and pyroptosis in the liver caused by bacteria, on the basis of CD38 deficiency. Overall, CD38 knockout exacerbates bacteria-induced liver damage through TLR4-NLRP3-GSDMD-mediated pyroptosis.

Novel Multiple miRNA-Based Signatures for Predicting Overall Survival and Recurrence-Free Survival of Colorectal Cancer Patients.

BACKGROUND Colorectal cancer (CRC) has become a heavy health burden around the world, accounting for about 10% of newly diagnosed cancer cases. In the present study, we aimed to establish the miRNA-based prediction signature to assess the prognosis of CRC patients. MATERIAL AND METHODS A total of 451 CRC patients' expression profiles and clinical information were download from the TCGA database. LASSO Cox regression was conducted to construct the overall survival (OS)- and recurrence-free survival (RFS)-associated prediction signatures, by which CRC patients were divided into low- and high-risk groups. Kaplan-Meier (K-M) curve and receiver operating characteristic (ROC) curves were used to explore the discriminatory ability and stability of the signatures. Functional enrichment analyses were performed to identify the probable mechanisms. RESULTS miRNA-216a, miRNA-887, miRNA-376b, and miRNA-891a were used to build the prediction formula associated with OS, while miR-1343, miR-149, miR-181a-1, miR-217, miR-3130-1, miR-378a, miR-542, miR-6716, miR-7-3, miR-7702, miR-677, and miR-891a were obtained to construct the formula related to RFS. K-M curve and ROC curve revealed the good discrimination and efficiency of OS in the training (P<0.001, AUC=0.712) and validation cohorts (P=0.019, AUC=0.657), as well as the results of RFS in the training (P<0.001, AUC=0.714) and validation cohorts (P=0.042, AUC=0.651). The function annotations for the targeted genes of these miRNAs show the potential mechanisms of CRC. CONCLUSIONS We established 2 novel miRNA-based prediction signatures of OS and RFS, which are reliable tools to assess the prognosis of CRC patients.

CHSY1 promoted proliferation and suppressed apoptosis in colorectal cancer through regulation of the NFκB and/or caspase-3/7 signaling pathway.

Colorectal cancer is a commonly observed malignant cancer. However, the limited therapies for colorectal cancer do not bring much benefit for patients. Chondroitin synthase-1 (CHSY1) is an enzyme responsible for the biosynthesis of chondroitin sulfate and has been implicated in the tumorigenesis of several cancer types; however, there is limited information regarding the role of CHSY1 in colorectal cancer. In the present study, CHSY1 was demonstrated to be highly expressed in colorectal cancer tissues and in cell lines, and the CHSY1 expression level was associated with the 5-year survival rate of patients with colorectal cancer. Following CHSY1 knockdown, the proliferation of colorectal cancer cells was significantly decreased. The number of RKO cells decreased by 50% following CHSY1 knockdown compared with that in the control after culture for 5 days. However, the apoptosis rate of RKO cells increased to 14.15% after CHSY1 knockdown. In addition, the activity of caspase-3/7 was also enhanced. Furthermore, the expression of B-cell lymphoma 2 (Bcl-2) was reduced, whereas the levels of Bcl-2-associated X protein (Bax) and truncated caspase-3/7 were increased following CHSY1 knockdown. Additionally, the phosphorylation level of IκB and the expression of nuclear factor (NF)κB also decreased. In contrast, forced expression of CHSY1 increased the level of Bcl-2, NFκB, and phosphorylated IκB, whereas the level of bax and truncated caspase-3/7 decreased. Therefore, the data of the present study suggest that CHSY1 promoted cell proliferation by regulating NFκB signaling and suppressed cell apoptosis by regulating/caspase-3/7 signaling in colorectal cancer. The present study also suggests that CHSY1 may be a potential target for colorectal cancer therapy.