Overall Survival In Colorectal Cancer Patients Research Articles

Identification of a lncRNA prognostic signature-related to stem cellindex and its significance in colorectal cancer.

Background: The relationship between long noncoding RNAs (lncRNAs) and themRNA stemness index (mRNAsi) in colorectal cancer (CRC) is still unclear. Materials & methods: The mRNAsi, mRNAsi-related lncRNAsand their clinical significance were analyzed by bioinformatic approaches in The Cancer Genome Atlas (TCGA)-COREAD dataset. Results: mRNAsi was negatively related to pathological features but positively related to overall survival and recurrence-free survival in CRC. A five mRNAsi-related lncRNAs prognostic signature was further developed and showed independent prognostic factors related to overall survival in CRC patients, due to the five mRNAsi-related lncRNAs involved in several pathways of the cancer stem cells and malignant cancer cell phenotypes. Conclusion: The present study highlights the potential roles of mRNAsi-related lncRNAs as alternative prognostic markers.

Clinicopathological Association of Autophagy Related 5 Protein with Prognosis of Colorectal Cancer.

Gene mutation and pathogenesis bacteria are highly associated with colorectal cancer (CRC) development and progression. Autophagy is a self-clearance pathway to degrade abnormal proteins and infected bacteria in cells. Autophagy plays a dual role in cancer development. Among the autophagy-related (ATG) proteins, ATG5 is the key component required for the core machinery of autophagy. However, the role of ATG5 in CRC malignancy remains unclear. Herein, we found that a high ATG5 protein level was correlated with poor overall survival (OS) and disease-free survival (DFS) of 118 patients with CRC. After stratification with demographic and clinicopathologic factors, a high ATG5 protein level was significantly correlated with unfavorable overall survival in female and elder (>60 year) CRC patients and tumor tissues with poor differentiation, late T stages (III + IV), whereas the ATG5 protein level was positively associated with the overall survival in CRC patients without lymph node invasion and radiation therapy. In contrast, a high ATG5 protein level was significantly associated with worse DFS in CRC patients with early stage of AJCC and no radiation therapy. In addition, colorectal cancer cells stably harboring small interfering RNA (siRNA) against ATG5 diminished the tumorsphere formation and sensitized cancer cells to chemotherapeutic agents. Taken together, our results suggest that ATG5 might be a prognostic biomarker for CRC and a potential therapeutic target for CRC patients.

The clinical significance of PD‑L1 in colorectal cancer (Review).

Colorectal cancer (CRC) is one of the most frequently encountered neoplasms and has a high rate of morbidity and mortality. Recent findings showing that tumor immune evasion is an important mechanism underlying propagation of a cancer have changed the landscape of medical oncology through identification of Programmed‑Death receptor1 and its ligand (PD‑1 and PD‑L1) as novel targets for oncological immune therapies. PD‑1 is primarily expressed on peritumoral lymphocytes and when activated, it suppresses its immune functions. Conversely, PD‑L1 is primarily expressed on the tumor infiltrating front with the purpose of deregulating physiological cytotoxic immune responses. Numerous studies have linked PD‑L1 overexpression to specific adverse clinicopathological features, such as poor differentiation, lymphovascular invasion and worse overall survival in CRC patients. Nevertheless, there is no concrete evidence showing which patients may exhibit the maximal beneficial effects of PD‑1/PD‑L1 blockade therapy, and how these novel molecular targets may be optimally integrated into therapeutic regimens for management of CRC patients with resectable and generalized disease.

Prognostic Risk Model of Immune-Related Genes in Colorectal Cancer.

PurposeWe focused on immune-related genes (IRGs) derived from transcriptomic studies, which had the potential to stratify patients’ prognosis and to establish a risk assessment model in colorectal cancer.SummaryThis article examined our understanding of the molecular pathways associated with intratumoral immune response, which represented a critical step for the implementation of stratification strategies toward the development of personalized immunotherapy of colorectal cancer. More and more evidence shows that IRGs play an important role in tumors. We have used data analysis to screen and identify immune-related molecular biomarkers of colon cancer. We selected 18 immune-related prognostic genes and established models to assess prognostic risks of patients, which can provide recommendations for clinical treatment and follow-up. Colorectal cancer (CRC) is a leading cause of cancer-related death in human. Several studies have investigated whether IRGs and tumor immune microenvironment (TIME) could be indicators of CRC prognoses. This study aimed to develop an improved prognostic signature for CRC based on IRGs to predict overall survival (OS) and provide new therapeutic targets for CRC treatment. Based on the screened IRGs, the Cox regression model was used to build a prediction model based on 18-IRG signature. Cox regression analysis revealed that the 18-IRG signature was an independent prognostic factor for OS in CRC patients. Then, we used the TIMER online database to explore the relationship between the risk scoring model and the infiltration of immune cells, and the results showed that the risk model can reflect the state of TIME to a certain extent. In short, an 18-IRG prognostic signature for predicting CRC patients’ survival was firmly established.

The Role of Cancer Stem Cells in Colorectal Cancer: From the Basics to Novel Clinical Trials.

Simple SummaryCancer stem cells (CSCs) fuel tumor growth, metastasis and resistance to therapy in colorectal cancer (CRC). These cells therefore represent a promising target for the treatment of CRC but are difficult to study because of the complexity of their isolation. This review presents the methods currently used to isolate colorectal CSCs as well as the techniques for characterizing these cells with their advantages and limitations. The aim of this review is to provide a state-of-the-art on the clinical relevance of CSCs in CRC by outlining current treatments for CRC, the resistance mechanisms developed by CSCs to overcome them, and ongoing clinical trials of drugs targeting CSCs in CRC. Overall, this review addresses the complexity of studying CSCs in CRC research and developing clinically effective treatments to enable CRC patients to achieve a short and long-term therapeutic response.The treatment options available for colorectal cancer (CRC) have increased over the years and have significantly improved the overall survival of CRC patients. However, the response rate for CRC patients with metastatic disease remains low and decreases with subsequent lines of therapy. The clinical management of patients with metastatic CRC (mCRC) presents a unique challenge in balancing the benefits and harms while considering disease progression, treatment-related toxicities, drug resistance and the patient’s overall quality of life. Despite the initial success of therapy, the development of drug resistance can lead to therapy failure and relapse in cancer patients, which can be attributed to the cancer stem cells (CSCs). Thus, colorectal CSCs (CCSCs) contribute to therapy resistance but also to tumor initiation and metastasis development, making them attractive potential targets for the treatment of CRC. This review presents the available CCSC isolation methods, the clinical relevance of these CCSCs, the mechanisms of drug resistance associated with CCSCs and the ongoing clinical trials targeting these CCSCs. Novel therapeutic strategies are needed to effectively eradicate both tumor growth and metastasis, while taking into account the tumor microenvironment (TME) which plays a key role in tumor cell plasticity.

The aging-related risk signature in colorectal cancer.

Background: Colorectal cancer (CRC) is the third most common cancer worldwide. The opening of the TCGA and GEO databases has promoted the progress of CRC prognostic assessment, while the aging-related risk signature has never been mentioned.Methods: R software packages, GSEA software, Venn diagram, Metascape, STRING, Cytoscape, cBioPortal, TIMER and GeneMANIA website were used in this study.Results: Aging-related gene sets, GO_AGING, GO_CELL_AGING and GO_CELLULAR_SENESCENCE, were activated significantly in CRC tissues. We constructed an aging-related risk signature using LASSO COX regression in training group TCGA and validated in testing group GSE39582. The risk score was significantly associated with the overall survival of CRC patients, whose stability was clarified by stratified survival analysis and accuracy was demonstrated using the ROC curve. The risk score was significantly increased in the advanced stage, T3-4, N1-3 and M1 and positively correlated with the richness of immune cell infiltration in the tumor microenvironment. We further investigated the molecular characteristics of 15 hub genes at the DNA and protein levels and performed GSEA between high- and low-risk groups.Conclusions: The aging-related signature is a reliable prognostic analysis model and can predict the severity and immune cell infiltration of CRC patients.

Prognostic value of pretreatment F-18 fluorodeoxyglucose PET/CT in colorectal cancer with unresectable metastasis.

The aim of the study was to assess the prognostic value of pretreatment PET/computed tomography (CT) scans in colorectal cancer (CRC) patients with unresectable metastasis. We retrospectively reviewed the pretreatment PET/CT images of 82 CRC patients with unresectable metastasis and their medical records. On PET/CT images, maximum standardized uptake value (SUVmax) of primary tumor, highest SUVmax of metastatic tumors and number of metastatic organs were identified. The patients were further divided into single and multiple organ metastases groups according to the extent of disease. Survival analysis was performed with the clinical variables and metabolic parameters from PET/CT. In a total of 82 patients, the age of patients, highest SUVmax of metastatic tumors and number of metastatic organs were independent prognostic factors for overall survival (OS) (all P < 0.05), whereas the SUVmax of primary tumor was not. On multivariate analysis, only the SUVmax of metastatic tumor was a significant prognostic factor in the single organ metastasis group (P = 0.047), whereas the age and highest SUVmax of metastatic tumors were independent prognostic factors in the multiple organ metastases group (all P < 0.05). The highest SUVmax of metastatic tumors was an independent prognostic factor for OS in CRC patients with unresectable metastasis.

Prognostic Prediction Models for Liver Metastasis and Overall Survival in Colorectal Cancer Patients

Objective The objective of this study was to develop novel prediction models for liver metastasis-free survival (LMFS) and overall survival (OS) in colorectal cancer (CRC) patients following surgically curative resections. We developed novel prediction models for LMFS and OS in CRC patients following surgically curative resections. Using clinicopathologic factors, such models were constructed with concordance indices of 0.811 and 0.776 for LMFS and OS, respectively. Methods Seven hundred seventy-six CRC patients presenting to the Osaka Medical Center for Cancer and Cardiovascular Diseases between January 2004 and December 2010 were retrospectively studied. The exclusion criteria were patients with preoperative treatment, synchronous distant metastasis, noncurative resection, and incomplete postoperative follow-up. Results Based on the analysis of clinicopathologic factors, the following factors had significant correlation with LMFS: preoperative serum carcinoembryonic antigen (pre-CEA), tumor invasion, lymph node metastasis, lymphatic invasion, and venous invasion. Using these variables, a novel prediction model was constructed by the Cox regression model with a concordance index (c-index) of 0.811 for LMFS. The following factors had a significant correlation with OS: age, pre-CEA, preoperative serum carbohydrate antigen 19-9, tumor location, pathologically defined tumor invasion, lymph node metastasis, and venous invasion. Using these variables, a prediction model was constructed with a c-index of 0.776 for OS. These models were validated by external datasets in an independent patient group. Conclusions We demonstrated the utility of a novel personalized prognostic model for liver metastasis, integrating tumor node metastasis factors, pre-CEA, and histologic lymphovascular invasion to predict the prognosis. Such models can help clinicians in treating CRC patients postoperatively.

Prognostic value of LINC02560 in colorectal cancer correlates with tumor microenvironment immunity.

Background: LINC02560 is a new 477 bp long non-coding RNA located in 19q13.43. However, the expression of LINC02560 in colorectal cancer (CRC) has not been reported, and its correlation with tumor development and function is still unclear.Methods: The expression of LINC02560 in CRC was first analyzed in the cancer genome atlas (TCGA) combined with The Genotype-Tissue Expression(GTEx) databases and then validated by clinical CRC samples and cell lines. The association between LINC02560 expression and clinicopathologic variables was analyzed by the Wilcoxon Rank SUM test. Cox regression analysis and Kaplan-Meier plots were used to assess the prognostic value of LINC02560 in CRC. The correlation between the expression level of LINC02560 and the 24 immune cells in tumor microenvironment (TME) was analyzed by single sample gene set enrichment analysis (ssGSEA). Gene set enrichment analysis (GSEA) was conducted to detect potential biological processes associated with LINC02560 in CRC.Results: LINC02560 was significantly up-regulated in CRC in comparison to normal samples. There are significant differences in the expression of LINC02560 in different subgroups of N stage, M stage, carcinoembryonic antigen (CEA) level, residual tumor, TP53 status and pathological stage. The high LINC02560 expression indicated poor overall survival (OS) and progress free interval (PFI) in patients with CRC. Moreover, the multivariate Cox analysis demonstrated that the expression of LINC02560 was an independent prognosis-predicting factor for OS in CRC patients. GSEA indicated that high expression of LINC02560 was involved in MAPK, Wnt, and PPAR signaling pathways and participated in humoral immune processes. We also identified that LINC02560 expression had a negative correlation with 4 kinds of immune cells.Conclusions: In summary, our research results indicate that LINC02560 may be a potential prognostic biomarker. It is involved in the occurrence and development of CRC and may affect the prognosis of CRC patients by regulating immune cells in the TME.

A novel 10-gene immune-related lncRNA signature model for the prognosis of colorectal cancer.

The tumor immune microenvironment of colorectal cancer (CRC) affects tumor development, prognosis and immunotherapy strategies. Recently, immune-related lncRNA were shown to play vital roles in the tumor immune microenvironment. The objective of this study was to identify lncRNAs involved in the immune response, tumorigenesis and progression of CRC and to establish an immune-related lncRNA signature for predicting the prognosis of CRC. We used data retrieved from the cancer genome atlas (TCGA) dataset to construct a 10-gene immune-related lncRNA pair (IRLP) signature model using a method based on the ranking and comparison of paired gene expression in CRC. The clinical prognosis, immune checkpoints and lncRNA-protein networks were analyzed to evaluate the signature. The signature was closely associated with overall survival of CRC patients (p < 0.001 in both of the training and validating cohorts) and the 3-year AUC values for the training and validating cohorts were 0.884 and 0.739, respectively. And, there were positive correlations between the signature and age (p = 0.048), clinical stage (p < 0.01), T stage (p < 0.01), N stage (p < 0.001) and M stage (p < 0.01). In addition, the signature model appeared to be highly relevant to some checkpoints, including CD160, TNFSF15, HHLA2, IDO2 and KIR3DL1. Further, molecular functional analysis and lncRNA-protein networks were applied to understand the molecular mechanisms underlying the carcinogenic effect and progression. The 10-gene IRLP signature model is an independent prognostic factor for CRC patient and can be utilized for the development of immunotherapy.

Identification of four novel prognosis biomarkers and potential therapeutic drugs for human colorectal cancer by bioinformatics analysis.

Colorectal cancer (CRC) is one of the most deadly cancers in the world with few reliable biomarkers that have been selected into clinical guidelines for prognosis of CRC patients. In this study, mRNA microarray datasets GSE113513, GSE21510, GSE44076, and GSE32323 were obtained from the Gene Expression Omnibus (GEO) and analyzed with bioinformatics to identify hub genes in CRC development. Differentially expressed genes (DEGs) were analyzed using the GEO2R tool. Gene ontology (GO) and KEGG analyses were performed through the DAVID database. STRING database and Cytoscape software were used to construct a protein-protein interaction (PPI) network and identify key modules and hub genes. Survival analyses of the DEGs were performed on GEPIA database. The Connectivity Map database was used to screen potential drugs. A total of 865 DEGs were identified, including 374 upregulated and 491 downregulated genes. These DEGs were mainly associated with metabolic pathways, pathways in cancer, cell cycle and so on. The PPI network was identified with 863 nodes and 5817 edges. Survival analysis revealed that HMMR, PAICS, ETFDH, and SCG2 were significantly associated with overall survival of CRC patients. And blebbistatin and sulconazole were identified as candidate drugs. In conclusion, our study found four hub genes involved in CRC, which may provide novel potential biomarkers for CRC prognosis, and two potential candidate drugs for CRC.

Prognostic impact of GPR56 in patients with colorectal cancer.

G protein-coupled receptor 56 (GPR56) belongs to the adhesion G protein-coupled receptor subfamily, which plays a role in cell progression and survival. The aim of this study was to investigate the role of the GPR56 gene in a cell line study and the impact of its protein expression on the prognosis of colorectal cancer (CRC) patients. The effect of GPR56 on tumor cell proliferation (WST-1 assay), invasion (Transwell assay), migration (Transwell assay, wound healing assay), and colony-forming ability (semisolid agar colony-forming assay) was explored. The expression levels of GPR56 in tissue samples of 109 CRC patients were evaluated by immunohistochemistry. The prognostic value of GRP56 was analyzed using univariate and multivariate analyses. The downregulation of GPR56 in the CRC cell line reduced cell proliferation as compared with that in a control sample (48 h; p=0.042, 72 h; p=0.001). Downregulation of the GPR56 expression reduced cell invasion and migration abilities and inhibited colony-forming abilities (p<0.005). The 5-year overall survival rate was worse in the high-expression group as compared with that in the low-expression group (51.6% vs. 74.4%, p=0.008). High GPR56 expression was a significant prognostic factor for overall survival of CRC patients in the univariate (p=0.001) and multivariate (p<0.001) analyses. The expression level of GPR56 plays an important role in tumor progression in CRC, and it may serve as a prognostic indicator in CRC patients.

Cetuximab enhances the anti-tumor function of macrophages in an IL-6 dependent manner

AimsCetuximab improves the survival of patients with advanced colorectal cancer (CRC). However, how cetuximab affects the tumor microenvironment has not been sufficiently understood. This study was to investigate whether cetuximab could inhibit the pro-tumor function of tumor-associated macrophages (TAMs) by suppressing the EGFR/IL-6 pathway. Main methodsThe azoxymethane/dextran sodium sulfate (AOM/DSS) and tumor xenograft mouse models were used to assess the effect of cetuximab on TAMs. Flow cytometry, Western blotting, RT-qPCR, and ELISA were used to assess the prevalence of M2 and M1 phenotypes. Publicly available datasets of CRC patients were used to assess the relevance of EGFR and IL-6 expression as prognostic indicators. Key findingsThe two mouse models showed that cetuximab could attenuate the pro-tumor function of TAMs and decrease tumor burden. Cetuximab repolarized TAMs from M2-like to M1-like phenotypes, mainly by suppressing the IL-6 expression through NFκB and STAT3 pathways. Analysis of public scRNA-seq data indicated EGFR was mainly expressed on the surface of macrophage infiltration into tumor microenvironment. The public transcriptomics datasets showed that the expression level of IL-6 was positively correlated with EGFR in CRC patients, and PROGgeneV2 analysis indicated that IL-6 and CD206 both predicted poor recurrence-free and overall survival of CRC patients. Furthermore, the inhibition efficacy of cetuximab was significantly attenuated in IL-6 knockout CRC mice model. SignificanceThese results indicate a new macrophage-based molecular mechanism explaining the effect of cetuximab in treatment of colorectal cancer.

Neoantigen Detection in Postoperative Colorectal Cancer Patients by Next-Generation Sequencing and Liquid Chromatography-Mass Spectrometry

Background/Aims: The new antigens are considered to be the best targets for anti-tumor T-cell immunity and individualized cancer immunotherapy strategies. The aim of this study is to explore tumor-specific neoantigen peptides produced by exon mutations of differentially expressed genes in postoperative colorectal cancer and their bioinformatics characteristics. Methods: The whole-genome sequencing of the tumor and paracancerous tissues and human leukocyte antigen class I (HLA-I) alleles of the tumor tissues was first detected by nextgeneration sequencing (NGS), tumor nascent antigen peptides were then predicted and identified according to exon mutations using liquid chromatography-mass spectrometry (LC-MS), and finally the affinity of nascent peptides with respective HLA I was calculate using NETMHC 4.0 Server. Differentially expressed genes producing neoantigens in colorectal cancer tissues were detected and the relationship between these genes and immune cells was screened through TIMER website. The mutation frequency and type of these genes were explored through CBioPortal website. The relationship between these genes and disease-free survival (DFS) and overall survival (OS) in colorectal cancer patients was explored through GEPIA website. Results: A total of 7 tumor-specific neoantigen peptides were identified from 4 patients, of which 3 showed certain affinity with HLA I. Frame-shift deletion, non frame-shift insertion and non frame-shift deletion were three main mutation types of exons. Most of the above-mentioned genes were differentially expressed in colorectal cancer, and some genes tended to express Individually in colorectal cancer. In addition to the type and amount of immune cells infiltrated in the tumor stroma, the expression intensity of these genes was also correlated with DFS and OS of colorectal cancer patients. Conclusion: The above results suggest that the type and number of tumor-specific neoantigens may be related to DFS and OS in postoperative colorectal cancer patients, and help predict the risk of postoperative recurrence, metastasis and prognosis.

The Development of Three-DNA Methylation Signature as a Novel Prognostic Biomarker in Patients with Colorectal Cancer.

Aims The prognosis of colorectal cancer (CRC) remains poor. This study aimed to develop and validate DNA methylation-based signature model to predict overall survival of CRC patients. Methods The methylation array data of CRC patients were retrieved from The Cancer Genome Atlas (TCGA) database. These patients were divided into training and validation datasets. A risk score model was established based on Kaplan-Meier and multivariate Cox regression analysis of training cohort and tested in validation cohort. Results Among total 14,626 DNA methylation candidate markers, we found that a three-DNA methylation signature (NR1H2, SCRIB, and UACA) was significantly associated with overall survival of CRC patients. Subgroup analysis indicated that this signature could predict overall survival of CRC patients regardless of age and gender. Conclusions We established a prognostic model consisted of 3-DNA methylation sites, which could be used as potential biomarker to evaluate the prognosis of CRC patients.

Prognostic Value of the Pretreatment Systemic Immune-Inflammation Index in Patients with Colorectal Cancer.

Background Multiple studies have reported the significance of the systemic immune-inflammation index (SII) in the prognosis of colorectal cancer (CRC), but no consensus has yet been reached. The purpose of this study was to systematically assess the prognostic value of SII in patients with CRC. Materials and Methods We performed a systematic literature search in PubMed, Embase, and the Cochrane Library for eligible studies. The correlation between pretreatment SII and overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) in CRC patients was evaluated by combining the hazard ratio (HR) and 95% confidence interval (CI). Results Twelve studies involving 3919 patients were included. Comprehensive analysis results showed that high SII indicated poor OS in CRC patients (HR = 1.777, 95% CI: 1.328-2.376). Compared with patients with low SII values, patients with high SII had lower PFS (HR = 1.658, 95% CI: 1.189-2.311). Subgroup analysis further verified the above results. Conclusions SII may be a noninvasive and powerful tool for predicting survival outcomes in CRC patients. However, more well-designed studies are needed to validate our findings.

Integrated Analysis of the Functions and Prognostic Values of RNA-Binding Proteins in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common malignant tumors. Selecting effective treatment for CRC patients, especially in the early stages, remains a challenge because of the lack of adequate biomarkers. Recent evidence suggests that RNA-binding proteins (RBPs) play a vital role in development and progression of carcinogenesis. However, their mechanisms in cancer progression are still limited. The role of RBPs in CRC has been poorly understood. There were 1,542 reported RBPs analyzed between CRC tissues and normal tissues using the Wilcoxon test to identify differentially expressed RBPs (DE RBPs). Then, the potential functions and the prognostic value of these DE RBPs were explored through systematic bioinformatics analysis. There were 177 DE RBPs identified between CRC tissues and normal tissues. A protein–protein interaction network was constructed based on DE RBPs, and critical modules were screened. A regulatory network between prognostic DE RBPs and differentially expressed transcription factors was constructed. Besides, a risk signature was built based on prognostic DE RBPs, which is able to predict overall survival of CRC patients with high accuracy. In conclusion, the results provided a comprehensive understanding of the functions of RBPs in CRC, as well as an RBP-related prognostic signature.

MiR-608 rs4919510 Polymorphism May Affect Susceptibility to Colorectal Cancer by Upregulating MRPL43 Expression.

There are many studies on the association between miR-608 rs4919510 polymorphism and susceptibility to colorectal cancer (CRC). However, the role of rs4919510 in CRC development and its underlying mechanism remain unclear. We first evaluated the gene that may be regulated by the variation of rs4919510 through a two-stage expression quantitative trait loci analysis and then compared the expression of that identified gene in CRC tissues and adjacent nontumor tissues. Next, methyl thiazolyl tetrazolium (MTT) assay, transwell assay, and flow cytometry analyses were performed to investigate the in vitro capacity of cell proliferation, migration, invasion, apoptosis, and cell cycle of CRC cells, respectively. Finally, through bioinformatics prediction, we contrasted the regulatory network and identified microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) that could regulate the obtained gene. We found that the variant G allele of rs4919510 located in miR-608 was associated with a potentially increased expression of MRPL43 in colon tissues (p = 0.065). Moreover, the results of functional experiments suggested that knockdown of the MRPL43 gene could inhibit the growth of the CRC HCT-116 cell line and promote apoptosis. Additionally, the cell cycle of CRC HCT-116 cell line was significantly arrested at the G2 phase. Next, we obtained a competing endogenous RNA regulatory network of MRPL43 with 17 pairs of miRNAs-lncRNAs by bioinformatics prediction, out of which, survival analysis indicated that different expression levels of miR-193b-3p (p = 0.0269) and miR-194-3p (p = 0.0113) were associated with overall survival in CRC patients. The rs4919510 variant G allele in miR-608 may increase the proliferation, invasion, and migration ability and decrease the apoptosis of CRC HCT-116 cell line by upregulating the expression of MRPL43, ultimately may affect the risk of CRC. Moreover, miR-193b-3p and miR-194-3p that target MRPL43 may serve as potential predictive biomarkers of CRC survival.

Upregulated CNTN1 is associated with lymph node metastasis and poor prognosis of colorectal cancer.

Contactin1 (CNTN1), a member of the immunoglobulin superfamily, is known to correlate with tumor development and progression. Although recent studies have found that elevated CNTN1 has been demonstrated in some types of cancers, the expression and prognosis of CNTN1 in colorectal cancer (CRC) are unclear. Here, we aimed to determine the clinicopathological characteristics and prognostic role of CNTN1 in CRC patients. The protein expression of CNTN1 in tumor tissues was evaluated by immunohistochemistry. In addition, the mRNA and protein expressions of CNTN1 were examined by qRT-PCR and Western blotting analysis in 40 matched adjacent normal mucosa samples. The relationships of CNTN1 with clinicopathological data and prognosis significance were analyzed. Immunohistochemical consequence suggested that the protein level of CNTN1 was obviously raised in CRC compared with adjacent normal mucosa tissues (56.9% vs 10.3%, P< 0.05). In addition, we detected a significant increase in CNTN1 mRNA and protein levels in CRC tissues compared with the matched adjacent normal mucosa tissues. Moreover, increased CNTN1 exprssion was significantly associated with tumor size, lymph node metastasis (LNM), tumor node-metastasis (TNM) stage and carcino-embryonic antigen (CEA) in clinical analysis. Kaplan-Meier analysis suggested that patients with CNTN1 over-expression showed worse overall survival (OS) (P= 0.001). Multivariate analysis indicated that high CNTN1 expression was an independent predictor for poor OS in CRC patients (P= 0.028). Further analysis revealed that patients with high CNTN1 combined with LNM present accurately predicted poorer outcome. Taken together, the findingsindicate that CNTN1 plays a significant role and serve as a potential biomarker for the prediction of adverse prognosis in CRC. Intriguingly, high express of CNTN1 + LNM-present combination may improve the accuracy of prognosis.

LPS Enhances the Chemosensitivity of Oxaliplatin in HT29 Cells via GSDMD-Mediated Pyroptosis.

IntroductionPyroptosis induced by lipopolysaccharide (LPS) is a dissolved form of cell death. The molecular marker gasdermin D, specifically GSDMD-N, is critically required for the induction of pyroptosis. Recently, there have been studies showing that LPS is closely related to tumor biology.MethodsSpecimens from 40 patients with colorectal cancer (CRC) were collected. Eight- to twelve-week-old C57BL6 male mice (n=30) were raised. Immunohistochemistry and Western blot were performed to test the expression of GSDMD. Moreover, cytotoxicity assay, IL-18 and IL-1β ELISA, Annexin V and PI stain, and wound healing assay were also made. Gene Expression Profiling Interactive Analysis (GEPIA) was used to verify the expression of GSDMD and overall survival of CRC patients with a high/low expression of GSDMD.ResultsIn the research, we showed that the poor prognosis in CRC patients was significantly related to the GSDMD expression and significantly down-regulated in human colorectal cancer (CRC) tissues. Treatment with LPS, but not TNF-α, induced pyroptosis via promoting the expression of GSDMD and GSDMD-N membrane translocation and enhanced chemosensitivity in response to L-OHP in HT29 cells. Furthermore, the enforced expression of GSDMD in HT29 cells reduced cell survival and induced cell death.DiscussionThese results of studies suggest that the low expression of GSDMD correlates with a poor CRC prognosis, and that pyroptosis induced by LPS may improve the anti-cancer effect of L-OHP, inhibiting the tumorigenesis of CRC by activating GSDMD. Our findings lay the foundation for further development of GSDMD serving as an important prognostic biomarker and a valid CRC therapeutic target.