LINC00858 facilitates formation of hepatic metastases from colorectal cancer via regulating the miR-132-3p/IGF2BP1 axis.

Hepatic metastasis is a major cause of colorectal cancer (CRC)-related deaths. Presently, the role of long non-coding RNAs (lncRNAs) in hepatic metastases from CRC is elusive. We dissected possible interplay between LINC00858/miR-132-3p/IGF2BP1 via bioinformatics approaches. Subsequently we analyzed mRNA expression of LINC00858, miR-132-3p and IGF2BP1 through qRT-PCR. Western blot was used to detect protein expression of IGF2BP1. RNA immunoprecipitation chip and dual-luciferase assay validated interaction between LINC00858 and miR-132-3p, as well as miR-132-3p and IGF2BP1. Cell viability, invasion, and migration were examined via CCK-8, colony formation, transwell and wound healing assays. Effect of LINC00858 on CRC hepatic metastases was validated via in vivo assay. Upregulated LINC00858 and IGF2BP1, and downregulated miR-132-3p were predicted in tumor tissues of patients with hepatic metastases from CRC. There were targeting relationships between LINC00858 and miR-132-3p, as well as miR-132-3p and IGF2BP1. Besides, LINC00858 facilitated progression of CRC cells. Rescue assay suggested that silencing LINC00858 suppressed CRC cell progression, while further silencing miR-132-3p or overexpressing IGF2BP1 reversed such effects. LINC00858 could facilitate CRC tumor growth and hepatic metastases. LINC00858 induced CRC hepatic metastases via regulating miR-132-3p/ IGF2BP1, and this study may deliver a new diagnostic marker for the disease.

Predicting mechanism of immune response in microsatellite instability colorectal cancer.

Colorectal cancer (CRC), also known as colon cancer, is the third most common cancer and the fourth most cause of cancer-related death in the world. CRC can be classified into two major subtypes, including microsatellite instability (MSI) and microsatellite stability (MSS), which showed different characteristics in immunotherapy. Low sensitivity of diagnostic biomarkers and metastasis are still the principal cause of mortality, especially in MSI. Here, applying computational programs, we identified recurring expression programs based on single cell RNA sequencing (scRNA-Seq) data of CRC cell lines. Notably, three MSI specific recurring modules were identified by non-negative matrix factorization (NMF). High NMF score genes enriched in the function of metabolism and inflammatory response. Focusing on top specific active transcription factor (TF), RUNX3 (Runt-related transcription factor 3), our results suggest that T cell infiltration was increased in RUNX3 high MSI CRC samples. Unbiased Gene Set Enrichment Analysis (GSEA) showed that RUNX3 was strongly associated with immune and metastasis related functions, such as Interferon Gamma (IFN-γ) and EPITHELIAL MESENCHYMAL TRANSITION (EMT). In addition, RUNX3 shows specific highly activated at epigenetic level in MSI compared with other gastrointestinal carcinomas. Positive correlation between RUNX3 and most immune checkpoints further confirmed RUNX3 might have crucial roles in MSI cancer progression and immunotherapy. Taken together, these results indicate significant tumor heterogeneity of two CRC subtypes at single-cell level and epigenetic modification level. These results also linked transcriptional dysregulation with immune infiltration at single-cell level in MSI, which may advance the application of scRNA-Seq technology in immunotherapy and contribute to developing novel biomarkers of this malignancy.

A Novel Esophagogastrostomy Technique for Laparoscopic Proximal Gastrectomy: Conical Remnant Gastroesophageal Side-overlap Fundoplication.

Background: There is currently no universally-accepted, ideal method of esophagogastric reconstruction to address reflux esophagitis and anastomotic complications of esophagogastrostomy after proximal gastrectomy. Case Report: In June 2022, two patients with Siewert type II carcinoma of esophagogastric junction underwent laparoscopic proximal gastrectomies, using a novel esophagogastrostomy technique of Conical remnant GastroEsophageal side-Overlap fundoplication (CGEO). On postoperative day 4, upper gastrointestinal fluoroscopy was performed, with patients in downward and left oblique positions, allowing gastrografin to accumulate within fundic reconstructions. No reflux into the esophagus was subsequently observed, and both patients were discharged (postoperative days 9 and 11). Six months after surgery, endoscopic view showed that the reconstructed cardia returned to its normal state, in the absence of any reflux symptoms. As of April 2023, we have operated on four patients using CGEO, and all of them recovered without obvious reflux symptoms. Conclusion: CGEO is a feasible and safe reconstructive esophagogastrostomy procedure following laparoscopic proximal gastrectomy for Siewert type II esophagogastric junction carcinoma.

Prognostic Factors in Stage IV Colorectal Cancer Patients With Resection of Liver and/or Pulmonary Metastases: A Population-Based Cohort Study.

Importance: Currently, surgical resection of distant metastatic lesions has become the preferred treatment for select colorectal cancer (CRC) patients with liver metastasis (LM) and/or pulmonary metastasis (PM). Metastasectomy is the most common curative method. However, evidence of the factors affecting the prognosis of CRC patients after resection of LM and/or PM is still insufficient. Objective: To explore the prognostic factors of CRC patients with LM and/or PM who have undergone resection of metastatic tumors and to provide reliable selection factors for surgical treatment in patients affected by LM and/or PM from CRC. Methods: The SEER database was used to identify eligible CRC LM and/or PM patients who underwent resection of the primary tumor and distant metastases from January 1, 2010, to December 31, 2018. The Kaplan-Meier method was used to calculate survival, and comparisons were performed using the log-rank test for univariate analysis. A Cox proportional hazards regression model was used to identify prognostic factors for the multivariate analysis. The outcomes included overall survival (OS) and cancer-specific survival (CSS). Results: A total of 3,003 eligible colorectal cancer patients with LM and/or PM were included in this study. The 3-year and 5-year OS rates were 53% and 33.6%, respectively, and the 3-year and 5-year CSS rates were 54.2% and 35.3%, respectively. In the adjusted multivariate analysis, age < 65 years (OS: p=0.002, CSS: p=0.002) was associated with better long-term outcomes, and primary tumors located on the left side of the colon (OS: p=0.004, CSS: p=0.006) or rectum (OS: p=0.004, CSS: p=0.006), T3 stage (OS: p<0.001, CSS: p<0.001), number of regional lymph nodes examined ≥ 12 (OS: p<0.001, CSS: p=0.001), and CRC LM (OS: p<0.001, CSS: p<0.001) were positive prognostic factors for survival after resection of metastatic tumors. Conclusion: Age < 65 years is associated with better long-term outcomes in colorectal cancer patients with LM and/or PM, analogously to the left sided primary tumor, T3 stage, number of regional lymph nodes examined ≥ 12 and liver metastases.

Metabolomic Profiling Identified Serum Metabolite Biomarkers and Related Metabolic Pathways of Colorectal Cancer.

BACKGROUND: The screening and early detection of colorectal cancer (CRC) still remain a challenge due to the lack of reliable and effective serum biomarkers. Thus, this study is aimed at identifying serum biomarkers of CRC that could be used to distinguish CRC from healthy controls. METHODS: A prospective 1 : 2 individual matching case-control study was performed which included 50 healthy control subjects and 98 CRC patients. Untargeted metabolomic profiling was conducted with liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify CRC-related metabolites and metabolic pathways. RESULTS: In total, 178 metabolites were detected, and an orthogonal partial least-squares-discriminant analysis (OPLS-DA) model was useful to distinguish CRC patients from healthy controls. Nine metabolites showed significantly differential serum levels in CRC patients under the conditions of variable importance in projection (VIP) > 1, p < 0.05 using Student's t-test, and fold change (FC) ≥ 1.2 or ≤0.5. The above nine metabolites were 3-hydroxybutyric acid, hexadecanedioic acid, succinic acid semialdehyde, 4-dodecylbenzenesulfonic acid, prostaglandin B2, 2-pyrocatechuic acid, xanthoxylin, 12-hydroxydodecanoic acid, and formylanthranilic acid. Four potential biomarkers were identified to diagnose CRC through ROC curves: hexadecanedioic acid, 4-dodecylbenzenesulfonic acid, 2-pyrocatechuic acid, and formylanthranilic acid. All AUC values of these four serum biomarkers were above 0.70. In addition, the exploratory analysis of metabolic pathways revealed the activated states for the vitamin B metabolic pathway and the alanine, aspartate, and glutamate metabolic pathways associated with CRC. CONCLUSION: The 4 identified potential metabolic biomarkers could discriminate CRC patients from healthy controls, and the 2 metabolic pathways may be activated in the CRC tissues.

S­allyl­cysteine sulfoxide (alliin) alleviates myocardial infarction by modulating cardiomyocyte necroptosis and autophagy.

S­allyl­cysteine sulfoxide (alliin) is the main organosulfur component of garlic and its preparations. The present study aimed to examine the protective effect of alliin on cardiac function and the underlying mechanism in a mouse model of myocardial infarction (MI). Notably, alliin treatment preserved heart function, attenuated the area of infarction in the myocardium of mice and reduced lesions in the myocardium, including cardiomyocyte fibrosis and death. Further mechanistic experiments revealed that alliin inhibited necroptosis but promoted autophagy in vitro and in vivo. Cell viability assays showed that alliin dose­dependently reduced the necroptotic index and inhibited the expression of necroptosis­related receptor­interacting protein 1, receptor­interacting protein 3 and tumor necrosis factor receptor­associated factor 2, whereas the levels of Beclin 1 and microtubule­associated protein 1 light chain 3, which are associated with autophagy, exhibited an opposite trend upon treatment with alliin. In addition, the level of peroxisome proliferator­activated receptor γ was increased by alliin. Collectively, these findings demonstrate that alliin has the potential to protect cardiomyocytes from necroptosis following MI and that this protective effect occurs via the enhancement of autophagy.