Lymph Node Metastasis In Colorectal Cancer Research Articles

Translation regulatory long non-coding RNA 1 represents a potential prognostic biomarker for colorectal cancer.

Long non-coding RNAs (lncRNAs) have attracted a lot of attention for their role in the development, progression and prognosis of colorectal cancer (CRC). However, little is known on the clinical significance of the translation regulatory lncRNA 1 (TRERNA1) in CRC. The present study aimed to explore the clinical value of TRERNA1 in patients with CRC. A total of 89 cancer-associated lncRNA genes were analyzed using the RT2 lncRNA PCR array Human Cancer PathwayFinder. Following the PCR array, reverse transcription-quantitative (RT-q)PCR was conducted to identify the differential expression of TRERNA1 between 130 CRC and corresponding non-tumorous adjacent tissues. Additionally, the association between TRERNA1 expression and clinical characteristics was analyzed. Furthermore, TRERNA1 expression was knocked down via small interfering RNAs. The results of the PCR array and RT-qPCR revealed that TRERNA1 expression was significantly upregulated in CRC tissues compared with in adjacent normal tissues. TRERNA1 upregulation was positively associated with distant metastasis, perineural invasion, TNM stage, node metastasis stage and tumor diameter. Multivariate analysis revealed that patients with higher TRERNA1 expression had a shorter overall survival (OS) time and a less favorable prognosis compared with those in the low TRERNA1 expression group. Knockdown of TRERNA1 inhibited invasion and metastasis of CRC cells via regulating Snail expression. In conclusion, TRERNA1 expression was upregulated in CRC tissues. High expression levels of TRERNA1 may be associated with poor OS times, a less favorable prognosis and lymph node metastasis in patients with CRC. TRERNA1 may therefore serve as a useful and novel biomarker for CRC lymph node metastasis and prognosis.

20(S)-ginsenoside Rh2 as agent for the treatment of LMN-CRC via regulating epithelial-mesenchymal transition.

The lymph node metastasis of colorectal cancer (LMN-CRC) seriously threatens the prognosis of patients. Chemotherapy, as the most common treatment, results in severe bone marrow suppression. 20(S)-ginsenoside Rh2 (SGRh2), a major effective constituent of ginseng, has demonstrated therapeutic effects on a variety of diseases, including some tumours. SGRh2 treatment had no effect on other organs. Therefore, ginsenosides are considered a safe and effective antineoplastic drug. However, the effects of SGRh2 on LMN-CRC remain unknown. The present study investigated the potential effect of SGRh2 on LMN-CRC in vitro and in vivo. SW480 and CoLo205 cell lines were treated with SGRh2. SGRh2 dose-dependently decreased CRC cell proliferation by CCK-8, colony formation and Edu assays. The Transwell and scratch assays revealed that SGRh2 inhibits the migratory and invasive abilities of CRC cells in a dose-dependent manner. Furthermore, the results of Western blotting revealed that SGRh2 decreased the expression of matrix metalloproteinase (MMP)-2 and MMP9. In terms of the underlying mechanisms, SGRh2 regulates CRC metastasis by affecting epithelial–mesenchymal transition (EMT), which significantly up-regulated epithelial biomarkers (E-cadherin) and down-regulated mesenchymal biomarkers (N-cadherin and vimentin) and EMT transcriptional factors (Smad-3, Snail-1, and Twist-1). In vivo, SGRh2 significantly inhibited LMN-CRC without affecting other normal organs. Immunohistochemical results showed that SGRh2 treats LMN-CRC by regulating EMT. These results demonstrate that SGRh2 has therapeutic potential for LMN-CRC.

Inhibition of Y Box Binding Protein 1 Suppresses Cell Growth and Motility in Colorectal Cancer.

Although chemo- or radiotherapy is usually performed in patients with colorectal cancer, the response is highly variable in locally rectal cancer. Therefore, additional studies are needed on predictable markers and the molecular mechanisms of chemo- and radiotherapy. Y box binding protein 1 (YB1) is an oncoprotein that is aberrantly expressed in many cancers, including colorectal cancer. However, to date there are no targeting agents or strategies to inhibit YB1 expression. Here, we investigate the oncogenic function of YB1 in colorectal cancer and methods to control its expression. We observed that YB1 expression level is correlated with colorectal cancer survival rate. Moreover, YB1 overexpression was associated with colorectal cancer lymph node metastasis and invasion. We also found that radiation exposure increased YB1 expression, which led to radioresistant colorectal cancer, mediated through the activation of cancer stem cell marker CD44 and PI3K/AKT/mTOR signaling. This study revealed, by both in vitro and in vivo assays, that depletion of YB1 could reduce cell proliferation and motility in colorectal cancer. We further demonstrated that the PI3K/mTOR inhibitor BEZ235 suppressed YB1 expression and enhanced the cytotoxicity of radiation. In addition, combined treatment with BEZ235 and radiation showed a significant antitumor response in an in vivo mouse xenograft model. Taken together, our results provide evidence that the activation of YB1 is a major factor in radioresistance and suggest that targeting YB1-mediated signaling is a promising therapeutic strategy for colorectal cancer.

A clinical-radiomics nomogram for the preoperative prediction of lymph node metastasis in colorectal cancer

BackgroundAccurate lymph node metastasis (LNM) prediction in colorectal cancer (CRC) patients is of great significance for treatment decision making and prognostic evaluation. We aimed to develop and validate a clinical-radiomics nomogram for the individual preoperative prediction of LNM in CRC patients.MethodsWe enrolled 766 patients (458 in the training set and 308 in the validation set) with clinicopathologically confirmed CRC. We included nine significant clinical risk factors (age, sex, preoperative carbohydrate antigen 19-9 (CA19-9) level, preoperative carcinoembryonic antigen (CEA) level, tumor size, tumor location, histotype, differentiation and M stage) to build the clinical model. We used analysis of variance (ANOVA), relief and recursive feature elimination (RFE) for feature selection (including clinical risk factors and the imaging features of primary lesions and peripheral lymph nodes), established classification models with logistic regression analysis and selected the respective candidate models by fivefold cross-validation. Then, we combined the clinical risk factors, primary lesion radiomics features and peripheral lymph node radiomics features of the candidate models to establish combined predictive models. Model performance was assessed by the area under the receiver operating characteristic (ROC) curve (AUC). Finally, decision curve analysis (DCA) and a nomogram were used to evaluate the clinical usefulness of the model.ResultsThe clinical-primary lesion radiomics-peripheral lymph node radiomics model, with the highest AUC value (0.7606), was regarded as the candidate model and had good discrimination and calibration in both the training and validation sets. DCA demonstrated that the clinical-radiomics nomogram was useful for preoperative prediction in the clinical environment.ConclusionThe present study proposed a clinical-radiomics nomogram with a combination of clinical risk factors and radiomics features that can potentially be applied in the individualized preoperative prediction of LNM in CRC patients.

A Combined four-mRNA Signature Associated with Lymphatic Metastasis for Prognosis of Colorectal Cancer

Background: Colorectal cancer (CRC) is one of the most common malignant tumors in the world. Lymph node metastasis (LNM) is a common mode of metastasis of CRC. However, the combined mRNA biomarkers associated with LNM of CRC that can effectively predict CRC prognosis have not been reported yet.Methods: To identify biomarkers that are associated with LNM, we collected data from the The Cancer Genome Atlas (TCGA) database. The edgeR package was searched to seek LNM-related genes by comparisons between cancer samples and normal colorectal tissues and between LNM and non-LNM (NLNM) of CRC. Univariate and multivariate regression analysis of genes in the intersection to build gene signature associated with independent prognosis of CRC, and then verified by Kaplan-Meier curve and log-rank test, receiver operating characteristic (ROC) curve was used to determine the efficiency of survival prediction of our four-mRNA signature. Finally, the potential molecular mechanisms and properties of these gene signature were also explored with functional and pathway enrichment analysis.Results: 329 mRNAs were up-regulated in CRC tissues with LNM, and 8461 mRNAs were up-regulated in CRC tissues, the intersection is 100 mRNAs. After univariate and multivariate Cox regression analysis of 100 mRNAs, a novel four LNM related mRNAs (EPHA8, KRT85, GABRA3, and CLPSL1) were screened as independent prognostic indicators of CRC. Surprisingly, the four-mRNA signature can predict the prognosis of CRC patients independently of clinical factors andthe area under the curve (AUC) of the ROC is 0.730. The novel four-mRNA signature was used to identify high and low-risk groups. Stratified analysis indicated the risk score based on four-mRNA signature was an independent prognostic indicator for female, T3+T4, N1+N2 ,stage III+IV and patients with no new tumor event. Functional annotation of this risk model in high-risk patients revealed that pathways associated with neuroactive ligand-receptor interaction, estrogen signaling pathway, and steroid hormone biosynthesis.Conclusions: By conducting TCGA data mining, our study demonstrated that a four-mRNA signature associated with LNM can be used as a combined biomarker for independent prognosis of CRC.

Distribution of Regulatory T-Cells and Other Phenotypes of T-Cells in Tumors and Regional Lymph Nodes of Colorectal Cancer Patients.

Tumor microenvironments consist of many types of immune cells, in which regulatory T-cells (Tregs) are supposed to play important roles to suppress anti-tumor immunity. Regional lymph nodes are essential for antitumor immunity in colorectal cancer (CRC). In this study, we compared the diversity of phenotypes of T-cells in normal tissue and regional lymph nodes in order to determine the immunosuppressive mechanism of lymph node metastasis of CRC. Fifty patients were enrolled in this study, and paired samples (tumor tissue, normal tissue, and three regional lymph node samples and as well as non-regional lymph node samples) were obtained from each patient. In each paired-sample set, the proportions of different immune cell types and T-cells expressing immune checkpoint molecules were compared using flow cytometry. Higher proportions of Tregs [7.58% (4.94%-13.87%) vs. 1.79% (0.03%-5.36%), p<0.001] and lower proportions of INFγ-producing CD4-positive T (iCD4+) cells [21.49% (12.08%-27.35%) vs. 26.55% (15.65%-37.63%), p<0.001] were observed in tumor tissue than in normal mucosa. Parts of regional lymph nodes nearest the tumor had a greater proportion of Tregs [5.86% (4.18%-7.69%)] and lower proportions of iCD4+ [5.94% (3.51%-9.04%)] and INFγ-producing CD8-positive T (iCD8+) cells [21.93% (14.92%-35.90%)] than distant parts of regional lymph nodes and non-regional lymph nodes. Both immune-suppressing molecules (CTLA-4 and PD-1) and immune-promoting molecules (OX-40 and ICOS) tended to be highly expressed in tumor tissue and local lymph nodes. In patients with CRC, regional lymph nodes, especially the parts nearest the tumor, had a higher proportion of Tregs and other suppressive immunophenotypes of T-cells than those located more distantly.

Association of the tumour stroma percentage in the preoperative biopsies with lymph node metastasis in colorectal cancer

BackgroundPreoperative prediction of lymph node (LN) status is integral to determining the most appropriate treatment strategy for colorectal cancer (CRC). This study aimed to develop and validate a nomogram to predict LN metastasis in CRC preoperatively.MethodsA total of 530 patients were enrolled and divided into training and validation cohorts. The tumour stroma percentage (TSP) of the preoperative biopsies was assessed. The risk factors for LN metastasis were selected, and a nomogram was constructed subsequently. The performance of the nomogram was assessed by using the AUROC and the calibration curve, and then validated in the validation cohort.ResultsHigh TSP was significantly associated with LN metastasis in both the training and validation cohorts. Computed tomography (CT)-reported T stage, CT-reported LN status, preoperative tumour differentiation, carcinoembryonic antigen, carbohydrate antigen 19-9 and TSP were independent predictors of LN metastasis in CRC. A nomogram incorporating the six predictors was constructed. The nomogram yielded good discrimination and calibration, with an AUROC of 0.846 (95% CI: 0.807−0.886) and 0.809 (95% CI: 0.745−0.872) in the training and validation cohorts, respectively.ConclusionsAssessment of TSP in the preoperative biopsies provided additional information about the LN status. The nomogram was useful for tailored therapy in CRC preoperatively.

Over-expression of Nav1.6 channels is associated with lymph node metastases in colorectal cancer

Background and objectivesLymph node metastasis is a key factor in predicting and determining the prognosis of patients with colorectal cancer (CRC). Sodium channels are highly expressed in a variety of tumors and are closely related to tumor development, metastasis, and invasion. We investigated the relationship between the expressions of different subtypes of Nav channels and lymph node metastasis of CRC.MethodsReal-time PCR (RT-qPCR) was carried out to measure the expressions of different sodium channel subtypes, chemokine receptors (CCR2, CCR4, CCR7), and lymphocyte infiltration-related biomarkers (CD3e, CD8a, IL-2RA) in CRC tissues from 97 patients. The expressions of Nav1.5 and Nav1.6 in surgically isolated lymph nodes were detected by immunohistochemistry. Correlation analysis between expressions of different genes and lymph node metastasis was performed by two-tailed t test.ResultsNav1.1 and Nav1.6 were highly expressed in CRC tissues and positively correlated with CRC lymph node metastasis. Nav1.6 was also highly expressed in metastatic lymph nodes. Further analysis showed that the high expression of Nav1.6 was closely related to the one of CCR2\\CCR4 in tumor lymph node metastasis.ConclusionsThese results suggested that Nav1.6 might be a novel marker for CRC lymph node metastasis.

The Management of Recurrence within Six Months after Hepatic Resection for Colorectal Liver Metastasis

Background: Hepatectomy is currently recommended as the most reliable treatment for colorectal liver metastases. However, the association between the choice of treatment for recurrence and the timing of recurrence remains controversial. Methods: Two-hundred ninety-five patients who underwent hepatectomy were retrospectively analyzed for the risk factors and the outcomes for early recurrence within 6 months. The remnant liver volumes (RLVs) and laboratory data were measured postoperatively using multidetector computed tomography on days 7 and months 1, 2, and 5 after the operation. Results: Early recurrence developed in 88/295 patients (29.8%). Colorectal cancer lymph node metastasis, synchronous liver metastasis, and multiple liver metastases were independent risk factors for the occurrence of early recurrence (p < 0.001, 0.032, and 0.019, respectively). Patients with early recurrence had a poorer prognosis than did patients who developed later recurrence (p < 0.001). Patients who underwent surgery or other local treatment had better outcomes. The changes in RLV and laboratory data after postoperative month 2 were not significantly different between the 2 groups. Conclusion: Patients with early recurrence within 6 months had a poorer prognosis than did patients who developed later recurrence. However, patients who underwent repeat hepatectomy for recurrence had a better prognosis than did those who underwent other treatments, with good prospects for long-term survival.

Identification of a miRNA‑mRNA network associated with lymph node metastasis in colorectal cancer

Lymph node metastasis is an important step in the progression of colorectal cancer (CRC); however, the underlying mechanisms are still unknown. The aim of the present study was to identify the gene expression pattern during lymph node metastasis in CRC and to identify upstream microRNAs (miRNAs) to explore the underlying mechanisms in detail. A total of 305 differently expressed genes (DEGs) were identified, including 227 upregulated genes and 78 downregulated genes in lymph node metastasis. Pathway and process enrichment analysis demonstrated that DEGs were significantly enriched in ‘NABA CORE MATRISOME’, ‘extracellular matrix assembly’, ‘antimicrobial humoral response’ and ‘Toll-like receptor signaling’ pathways. The top 10 hub genes were identified by protein-protein interaction network, and sub-networks revealed that these genes were involved in significant pathways, including ‘neutrophil chemotaxis’ and ‘Smooth Muscle Contraction’. In addition, 73 mature differently expressed miRNAs associated with lymph node metastasis were identified, of which 48 were upregulated and 25 were downregulated. Six miRNAs were identified to regulate DEGs. Additionally, based on the relationship between miRNAs and transcription factors, a miRNA-TF-mRNA network was constructed. In conclusion, DEGs, miRNAs and their interactions and pathways were identified in lymph node metastasis in CRC, which provided insight into the mechanism of CRC metastasis and may be used to develop novel targets for CRC treatment.

Calcium-Activated Chloride Channel A4 (CLCA4) Plays Inhibitory Roles in Invasion and Migration Through Suppressing Epithelial-Mesenchymal Transition via PI3K/AKT Signaling in Colorectal Cancer.

BackgroundCalcium-activated chloride channel A4 (CLCA4) is known as a tumor suppressor which contributes to the progression of a number of types of malignant tumors. However, little is known about the functional roles of CLCA4 in colorectal cancer (CRC).Material/MethodsIn this study, the expression patterns and dysregulation of mRNAs in CRC tissues were profiled by analyzing GSE21510 datasets from Gene Expression Omnibus database which contains 104 primary hepatocellular carcinoma tissues and 24 normal liver tissues, and by performing Kaplan-Meier analysis of TCGA data. Additionally, immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR) were performed using clinical tissues collected at our institute. In order to explore the functional role of CLCA4, gain-of-function cell models were constructed in SW620 and LoVo cells. Wound healing assay and Transwell assay were carried out to access the cell migration and invasion ability.ResultsIt was found that CLCA4 was an independent predictor for overall survival and lymph node metastasis. Additionally, immunohistochemistry and qRT-PCR results of the clinical tissues collected as part of our study further confirmed this correlation. In vitro experiments demonstrated that over-expression of CLCA4 could inhibit cell migration and invasion by suppressing epithelial-mesenchymal transition (EMT) via PI3K/ATK signaling and change the expression patterns of EMT markers in CLCA4-gain-of-function cell models.ConclusionsCLCA4 inhibits migration and invasion by suppressing EMT via PI3K/ATK signaling and predicts favorable prognosis of CRC which may help to distinguish potential risk of lymph node metastasis in CRC.

Investigating the diagnostic performance of HOTTIP, PVT1, and UCA1 long noncoding RNAs as a predictive panel for the screening of colorectal cancer patients with lymph node metastasis.

Like other noncoding RNAs (ncRNAs), dysregulation of long ncRNAs (lncRNAs) has been associated with various clinicopathological features of colorectal cancer (CRC) patients such as lymph node metastasis (LNM). Recently, three aberrant expressed oncogenic lncRNA (onco-lncRNAs), including HOXA transcript at the distal tip (HOTTIP), plasmacytoma variant translocation 1 (PVT1), and urothelial carcinoma associated 1 (UCA1) have been reported in LNM. Herein, we compared the diagnostic performance of these lncRNAs as individual biomarkers and as a discriminating panel between LNM CRC patients, nonmetastatic lymph nodes (NLN) and normal healthy subjects. The lncRNAs expression level was measured by quantitative real-time PCR and analyzed by the Mann-Whitney U test. The receiver operating characteristic (ROC) curve analysis was applied to evaluate the diagnostic power. The Kaplan-Meier survival analysis was performed to outline the overall survival (OS) of CRC patients with an abnormal level of lncRNAs. The area under the ROC curve (AUC) of the overexpressed HOTTIP (0.7817; 95% CI, 0.6809-0.8824), PVT1 (0.8559; 95% CI, 0.7737-0.9382), and UCA1 (0.8135; 95% CI, 0.722-0.9051) introduced them as individual CRC biomarkers. As a predictive panel, the AUC values of the HOTTIP, PVT1, and UCA1 for training set were 0.9256 (95% CI, 0.8634-0.9879; all CRCs), 0.8708 (95% CI, 0.7709-0.9378; NLN) and 0.9804 (95% CI, 0.9585-0.9998; LNM), and for validation set were 0.9286 (95% CI, 0.8752-0.9820; all CRCs), 0.8911 (95% CI, 0.8238-0.9585; NLN), and 0.9833 (95% CI, 0.9642-1.002; LNM), respectively. Also, HOTTIP/PVT1/UCA1 panel dysregulation had a marked correlation with patient's OS in training set (logrank test P = 0.0121; hazard ratio [HR], 0.1225; 95% confidence interval [CI], 0.02376-0.6312), and in validation set (logrank test P < 0.0001, HR, 0.2003; 95% CI, 0.08942-0.4486). These data showed that the combination of HOTTIP, PVT1, and UCA1 as a predictive panel, has a better diagnostic performance than each of these lncRNAs individually, and could be used for the screening of patients with advanced CRC.

A Gene-Related Nomogram for Preoperative Prediction of Lymph Node Metastasis in Colorectal Cancer

Purpose: To develop and validate a gene-related nomogram for predicting the risk of lymph node (LN) metastasis preoperatively in patients with colorectal cancer (CRC). Methods: RNA-seq data of 581 CRC and 51 normal cases with clinical features were downloaded from TCGA database. In the evaluation cohort with 381 CRC cases, the LASSO regression was used to reduce dimensionality of gene signatures extracted to build gene score. A gene-related nomogram was performed based on the multivariable logistic regression analysis. The performance of the nomogram was assessed by the discrimination, calibration, and clinical usefulness not only in the evaluation, but also in the validation cohort with 200 CRC cases. Results: A total of 12,590 differentially expressed genes were selected, in which 59 candidates associated with LN metastasis in differentially expressed genes set were screened by LASSO to form the gene score. Based on the analysis of multivariate logistic regression, the gene-related nomogram showed good calibration and discrimination not only in the evaluation cohort (concordance-index 0.93; 95%CI 0.91–0.96), but also in the validation cohort (concordance-index 0.70; 95%CI 0.63–0.78). The decision curve analysis of the gene-related nomogram also provides constructive guidance for the design of operation plan, preoperatively. Conclusions: The presented genes nomogram may predict the LN metastasis in CRC patients, preoperatively. And 59 hub genes were defined related to LN metastasis of CRC, which can serve as treatment targets for the further study. Preoperative biopsy and gene analysis are needed to develop the operation plan in clinical practice.

The Relationship of CXCR1, IκBα and HIF-1α Expression Levels with Clinicopathological Parameters in Colorectal Cancer.

The role of C-X-C motif chemokine receptor 1 (CXCR1), inhibitor of kappa B (IκBα), and hypoxia-inducible factor 1 alpha (HIF-1α) have been reported to promote tumorigenesis and progression in colorectal cancer (CRC). This study is to evaluate the expression of CXCR1, IκBα, and hypoxia-inducible factor 1 alpha (HIF-1α), in combination, in CRC tissues. It also aims to analyze the relationship of these three factors with clinico-pathological characteristics. CRC and tumor-adjacent tissues were surgically collected from CRC patients. All patients were diagnosed by pathological examination, and none of the patients had received preoperative chemotherapy or radiotherapy. RNA extraction and cDNA synthesis were performed, and the transcription of CXCR1, IκBα, HIF-1α, and β-actin was quantified by RT-qPCR. The significant increase of CXCR1, HIF-1α, and decrease of IκBα mRNA expression level were observed in tumor samples of CRC patients (p < 0.05). In addition, CXCR1 expression level was correlated with lymph node metastasis (p = 0.013). Also, results demonstrated a relationship between HIF-1α expression and TNM stage and lymph node metastasis (p = 0.047 and p = 0.005, respectively). CXCR1 and HIF-1α simultaneous expression demonstrated the significant relationship with lymph node metastasis in CRC. Our findings indicated that CXCR1, HIF-1α, and IκBα can be used as potential prognostic factors indicating tumors in the advanced stage in patients with CRC.

Development of a preoperative prediction nomogram for lymph node metastasis in colorectal cancer based on a novel serum miRNA signature and CT scans.

BackgroundPreoperative prediction of lymph node (LN) status is of crucial importance for appropriate treatment planning in patients with colorectal cancer (CRC). In this study, we sought to develop and validate a non-invasive nomogram model to preoperatively predict LN metastasis in CRC.MethodsDevelopment of the nomogram entailed three subsequent stages with specific patient sets. In the discovery set (n = 20), LN-status-related miRNAs were screened from high-throughput sequencing data of human CRC serum samples. In the training set (n = 218), a miRNA panel-clinicopathologic nomogram was developed by logistic regression analysis for preoperative prediction of LN metastasis. In the validation set (n = 198), we validated the above nomogram with respect to its discrimination, calibration and clinical application.FindingsFour differently expressed miRNAs (miR-122-5p, miR-146b-5p, miR-186-5p and miR-193a-5p) were identified in the serum samples from CRC patients with and without LN metastasis, which also had regulatory effects on CRC cell migration. The combined miRNA panel could provide higher LN prediction capability compared with computed tomography (CT) scans (P < .0001 in both the training and validation sets). Furthermore, a nomogram integrating the miRNA-based panel and CT-reported LN status was constructed in the training set, which performed well in both the training and validation sets (AUC: 0.913 and 0.883, respectively). Decision curve analysis demonstrated the clinical usefulness of the nomogram.InterpretationOur nomogram is a reliable prediction model that can be conveniently and efficiently used to improve the accuracy of preoperative prediction of LN metastasis in patients with CRC.

Einfluss des primären Lymphknotenstatus kolorektaler Karzinome auf die Entwicklung von Lungenmetastasen und thorakalen Lymphknotenmetastasen

The lungs are the second most common organ site for metastases in patients with colorectal cancer (CRC). Lymph node metastasis of CRC represents aprognostic factor for survival. The present study investigated the influence of CRC lymph node metastasis on lung metastasis, in particular thoracic lymph node metastasis. A retrospective analysis of 88patients (n = 56male) with curative resection of lung metastases of CRC was performed. Primary endpoint: influence of lymph node status of CRC on lung metastases. Secondary endpoints: disease-free survival and overall survival. Statistical evaluation was carried out with SPSS. In 48patients apositive lymph node status of CRC and in 9patients an N+ status of lung metastases were determined. The lymph node status of the CRC significantly affected the incidence of synchronous metastases (p = 0.03), disease-free interval until formation of metachronous lung metastases (p = 0.012) and the overall survival of patients with CRC (p = 0.048). The 5‑year survival rate for CRC patients with lung metastases was 48.7% after pulmonary metastasectomy. Thoracic lymph node involvement also significantly affected survival (p = 0.001). Screening for pulmonary metastases should be included in the staging and follow-up of all patients with CRC, especially in patients with apositive lymph node status of the CRC.

Preoperative Prediction Nomogram Based on a Novel Serum miRNA Signature and CT Scans for Lymph Node Metastasis in Colorectal Cancer

Background: Preoperative prediction of lymph node (LN) status is of crucial importance for appropriate treatment planning in patients with colorectal cancer (CRC). Here, we sought to develop and validate a non-invasive nomogram model to preoperatively predict LN metastasis in CRC. Methods: In the discovery set (n=20), LN-status-related miRNAs were screened from high-throughput sequencing data of human CRC serum samples. In the training set (n=218), a miRNA panel-clinicopathologic nomogram was developed by logistic regression analysis for preoperative prediction of LN metastasis. In the validation set (n=198), we validated the above nomogram with respect to its discrimination, calibration and clinical application. Findings: We identified four differently expressed miRNAs (miR-122-5p, miR-146b-5p, miR-186-5p and miR-193a-5p), which, when combined in the miRNA-based panel, could provide higher LN prediction capability compared with computed tomography (CT) scans (P<0.05 in both training and validation sets). Furthermore, a nomogram integrating the miRNA-based panel and CT-reported LN status was constructed in the training set, which performed well in both training and validation sets (AUC: 0.913 and 0.883, respectively). Decision curve analysis demonstrated the clinical usefulness of the nomogram. Interpretation: Our nomogram is a reliable prediction model that can be conveniently and efficiently used to improve the accuracy of preoperative prediction of LN metastasis in patients with CRC. Funding: This project was supported by National Natural Science Foundation of China (Nos. 81472025, 81772271, 81601846, 81702084 and 81301506), Shandong Technological Development Project (2016CYJS01A02), Taishan Scholar Program of Shandong Province, Natural Science of Basic Scientific Research Foundation of Shandong University (2017BTS01), Science Foundation of Qilu Hospital of Shandong University (2015QLMS51) and Fundamental Research Funds of Shandong University (2014QLKY03). Declaration of Interest: The authors declare no potential conflicts of interest. Ethical Approval: Ethical approval was obtained for this retrospective study, and the informed consent requirement was waved.

LncRNA GAS5 inhibits colorectal cancer cell proliferation via the miR‑182‑5p/FOXO3a axis.

Long non‑coding RNAs(lncRNAs) are mainly involved in diverse biological processes in human malignancies. The expression profile and underlying mechanism of the lncRNA growth arrest specific transcript5(GAS5) in colorectal cancer(CRC) are poorly understood. Here, we investigated the role of GAS5 in human CRC tissues. lncRNA GAS5 was specifically downregulated in CRC tissues and cell lines. Reduced GAS5 levels were significantly associated with advanced clinical stage and lymph node metastasis in CRC. GAS5 overexpression suppressed CRC cell proliferation and promoted cellular apoptosis. A dual‑luciferase reporter assay showed that GAS5 could negatively regulate the expression of microRNA(miR)‑182‑5p. Upregulated miR‑182‑5p abrogated the effect of GAS5 overexpression on CRC cell proliferation and apoptosis. Furthermore, GAS5 positively regulated the expression of FOXO3a in CRC cells. Taken together, these findings suggest that overexpression of the lncRNA GAS5 inhibits cell proliferation and promotes apoptosis by inhibiting miR‑182‑5p expression, and thus could be a therapeutic target in CRC.

The expression and significance of CD(276) and CD(133) in colorectal cancer and precancerous lesions

In order to study the significance of CD(276) and CD(133) in the development and progression of colorectal cancer (CRC), the expression of CD(276) and CD(133) was detected by immunohistochemistry in CRC and precancerous lesions. The results showed that the intensity of CD(276) and CD(133) in CRC samples was higher than that in adenoma group and non-adenoma group. CD(276) and CD(133) single and double positive expression were significantly correlated with CRC lymph node metastasis, distant metastasis and survival. CD(276) and CD(133) are significantly correlated to the development and progression of CRC and associated with poor prognosis.

HER4 isoform CYT2 and its ligand NRG1III are expressed at high levels in human colorectal cancer.

The present study aimed to evaluate the expression of human epidermal growth factor receptor (HER4) isoforms and their ligand neuregulin 1 (NRG1) isoforms in human primary colorectal cancer (CRC). The mRNA expression of HER4 isoforms JM-a, JM-b, CYT1 and CYT2, and their ligand isoforms NRG1 I, II and III in CRC tissues and adjacent normal tissues were quantified by reverse transcription-quantitative polymerase chain reaction analysis. Univariate analysis and logistic regression analysis were performed to analyze the association between HER4 and NRG1 expression and lymph node metastasis in CRC. The expression levels of CYT1 (P=0.002), CYT2 (P=0.002) and NRG1 type III (P<0.001) were significantly higher in the CRC tissues than in the adjacent normal tissues. The expression of CYT2 was correlated with tumor stage (P=0.018), lymph node status (P=0.015) and tumor-node-metastasis (P=0.038) in CRC. The expression of NRG1III was correlated with lymph node metastasis, and the expression of CYT2 was associated with the expression of NRG1III (r=0.691, P<0.01). The logistic regression analysis indicated that expression of CYT2 >50 was a risk factor for lymph node metastasis in CRC. In conclusion the expression levels of CYT1, CYT2 and NRG1III were upregulated in CRC. An expression of CYT-2 >50 was identified as a risk factor for lymph node metastasis in CRC. Therefore, CY-2 and NRG1III may be involved in the progression of CRC.