MTUS1 is a promising diagnostic and prognostic biomarker for colorectal cancer.

BACKGROUND: The morbidity and mortality of colorectal cancer (CRC) remain high, posing a serious threat to human life and health. The early diagnosis and prognostic evaluation of CRC are two major challenges in clinical practice. MTUS1 is considered a tumour suppressor and can play an important role in inhibiting cell proliferation, migration, and tumour growth. Moreover, the expression of MTUS1 is decreased in different human cancers, including CRC. However, the biological functions and molecular mechanisms of MTUS1 in CRC remain unclear. METHODS: In the present study, data from The Cancer Genome Atlas (TCGA) database were analysed using R statistical software (version 3.6.3.) to evaluate the expression of MTUS1 in tumour tissues and adjacent normal tissues using public databases such as the TIMER and Oncomine databases. Then, 38 clinical samples were collected, and qPCR was performed to verify MTUS1 expression. We also investigated the relationship between MTUS1 expression and clinicopathological characteristics and elucidated the diagnostic and prognostic value of MTUS1 in CRC. In addition, the correlation between MTUS1 expression and immune infiltration levels was identified using the TIMER and GEPIA databases. Furthermore, we constructed and analysed a PPI network and coexpression modules of MTUS1 to explore its molecular functions and mechanisms. RESULTS: CRC tissues exhibited lower levels of MTUS1 than normal tissues. The logistic regression analysis indicated that the expression of MTUS1 was associated with N stage, TNM stage, and neoplasm type. Moreover, CRC patients with low MTUS1 expression had poor overall survival (OS). Multivariate analysis revealed that the downregulation of MTUS1 was an independent prognostic factor and was correlated with poor OS in CRC patients. MTUS1 expression had good diagnostic value based on ROC analysis. Furthermore, we identified a group of potential MTUS1-interacting proteins and coexpressed genes. GO and KEGG enrichment analyses showed that MTUS1 was involved in multiple cancer-related signalling pathways. Moreover, the expression of MTUS1 was significantly related to the infiltration levels of multiple cells. Finally, MTUS1 expression was strongly correlated with various immune marker sets. CONCLUSIONS: Our results indicated that MTUS1 is a promising biomarker for predicting the diagnosis and prognosis of CRC patients. MTUS1 can also become a new molecular target for tumour immunotherapy.

Immune landscape and prognostic immune-related genes in KRAS-mutant colorectal cancer patients.

BACKGROUND: KRAS gene is the most common type of mutation reported in colorectal cancer (CRC). KRAS mutation-mediated regulation of immunophenotype and immune pathways in CRC remains to be elucidated. METHODS: 535 CRC patients were used to compare the expression of immune-related genes (IRGs) and the abundance of tumor-infiltrating immune cells (TIICs) in the tumor microenvironment between KRAS-mutant and KRAS wild-type CRC patients. An independent dataset included 566 cases of CRC and an in-house RNA sequencing dataset were served as validation sets. An in-house dataset consisting of 335 CRC patients were used to analyze systemic immune and inflammatory state in the presence of KRAS mutation. An immue risk (Imm-R) model consist of IRG and TIICs for prognostic prediction in KRAS-mutant CRC patients was established and validated. RESULTS: NF-κB and T-cell receptor signaling pathways were significantly inhibited in KRAS-mutant CRC patients. Regulatory T cells (Tregs) was increased while macrophage M1 and activated CD4 memory T cell was decreased in KRAS-mutant CRC. Prognosis correlated with enhanced Tregs, macrophage M1 and activated CD4 memory T cell and was validated. Serum levels of hypersensitive C-reactive protein (hs-CRP), CRP, and IgM were significantly decreased in KRAS-mutant compared to KRAS wild-type CRC patients. An immune risk model composed of VGF, RLN3, CT45A1 and TIICs signature classified CRC patients with distinct clinical outcomes. CONCLUSIONS: KRAS mutation in CRC was associated with suppressed immune pathways and immune infiltration. The aberrant immune pathways and immune cells help to understand the tumor immune microenvironments in KRAS-mutant CRC patients.

SATB2 suppresses gastric cancer cell proliferation and migration.

Gastric cancer is one of the death-related malignant tumors worldwide. It remains a challenge for the diagnosis and treatment of gastric cancer. Special AT-rich sequence-binding protein 2 (SATB2) is a new tumor suppressive gene and plays important roles in many cancers. However, the role of SATB2 in gastric cancer is still unknown. In the present study, we demonstrated that downregulation of SATB2 was associated with shortened survival in patients with gastric cancer. Ectopic expression of SATB2 inhibited gastric cancer cell proliferation, colony formation, and migration. Overexpression of SATB2 repressed the expression of extracellular signal-regulated kinase 5 (ERK5), and activation of ERK5 restored the SATB2-induced inhibition of proliferation and migration in gastric cancer. This study provided evidence that SATB2 acted as a tumor suppressive gene gastric cancer, serving as a potential therapeutic target.

Multi-omics analyses of glucose metabolic reprogramming in colorectal cancer.

Background: Glucose metabolic reprogramming (GMR) is a cardinal feature of carcinogenesis and metastasis. However, the underlying mechanisms have not been fully elucidated. The aim of this study was to profile the metabolic signature of primary tumor and circulating tumor cells from metastatic colorectal cancer (mCRC) patients using integrated omics analysis. Methods: PET-CT imaging, serum metabolomics, genomics and proteomics data of 325 high 18F-fluorinated deoxyglucose (FDGhigh) mCRC patients were analyzed. The para-tumor, primary tumor and liver metastatic tissues of mCRC patients were used for proteomics analysis. Results: The glucose uptake in tumor tissues as per the PET/CT images was correlated to serum levels of glutamic-pyruvic transaminase (ALT), total bilirubin (TBIL), creatinine (CRE). Proteomics analysis indicated that several differentially expressed proteins were enriched in both GMR and epithelial-mesenchymal transition (EMT)-related pathways. Using a tissue-optimized proteomic workflow, we identified novel proteomic markers (e.g. CCND1, EPCAM, RPS6), a novel PCK1-CDK6-INSR protein axis, and a potential role for FOLR (FR) in GMR/EMT of CRC cells. Finally, CEA/blood glucose (CSR) was defined as a new index, which can be used to jointly diagnose liver metastasis of colorectal cancer. Conclusions: GMR in CRC cells is closely associated with the EMT pathway, and this network is a promising source of potential therapeutic targets.

Oral-Intestinal Microbiota in Colorectal Cancer: Inflammation and Immunosuppression.

It is widely recognized that microbial disorders are involved in the pathogenesis of many malignant tumors. The oral and intestinal tract are two of the overriding microbial habitats in the human body. Although they are anatomically and physiologically continuous, belonging to the openings at both ends of the digestive tract, the oral and intestinal microbiome do not cross talk with each other due to a variety of reasons, including intestinal microbial colonization resistance and chemical barriers in the upper digestive tract. However, this balance can be upset in certain circumstances, such as disruption of colonization resistance of gut microbes, intestinal inflammation, and disruption of the digestive tract chemical barrier. Evidence is now accruing to suggest that the oral microbiome can colonize the gut, leading to dysregulation of the gut microbes. Furthermore, the oral-gut microbes create an intestinal inflammatory and immunosuppressive microenvironment conducive to tumorigenesis and progression of colorectal cancer (CRC). Here, we review the oral to intestinal microbial transmission and the inflammatory and immunosuppressive microenvironment, induced by oral-gut axis microbes in the gut. A superior comprehension of the contribution of the oral-intestinal microbes to CRC provides new insights into the prevention and treatment of CRC in the future.

Evaluation of colorectal cancer liver metastases based on liquid biopsy combined with folate receptor- Positive circulating tumor cells and HSP90.

Objective: Liver metastasis of colorectal cancer (LMCRC) is a major cause of cancer-related deaths worldwide. We can reduce the mortality rate by discerning the risk of liver metastases in patients with colorectal cancer at an early stage. Hence, we combined the use of folate receptor (FR)-labeled circulating tumor cells (FR+CTCs) and the metastasis-related marker, heat shock protein 90 (HSP90), to screen patients with colorectal cancer and explore the prognostic factors of patients with high expression of FR+CTC and HSP90. Patients and methods: A retrospective study of 356 patients with measurable colorectal cancer was performed. Negative enrichment and FR-targeted fluorescence quantitative PCR was utilized to detect FR+CTC. An ELISA kit was used to detect HSP90 expression. A timely follow-up study of patients with colorectal cancer was made. Results: Colorectal patients with liver metastases showed high expression of FR+CTCs and HSP90. The diagnostic ability of the combined receiver operating characteristic curve of FR+CTC and HSP90 (area under the curve [AUC]=0.79, sensitivity 70.55%, specificity 92.66%) was significantly greater than that of a single index. The results of timely follow-up of patients showed that the high expression of FR+CTC significantly shortened the median disease-free survival (mDFS) of 36.5 months (95% confidence interval [CI]: 14.13-58.87, Logrank p < 0.0001) compared with the low expression cohort. The mDFS of the HSP90 high-expression cohort was significantly higher than that of the low-expression cohort (Logrank p = 0.0002), mDFS=58.47 months (95% CI: 37.12-79.81, Logrank p < 0.0001). We performed univariate and multivariate analyses to show that FR+CTC and HSP90 were risk factors for the progression of metastatic colorectal cancer (MCRC) disease. We then constructed a high- and low-risk score model of risk factors to evaluate MCRC. The diagnostic sensitivity of the risk model for MCRC was significantly improved (AUC=0.89, sensitivity 85.29%, specificity 81.33%), and the mDFS of patients in a high-risk group increased to 33.28 months (95% CI: 27.24-39.31, Logrank p < 0.0001). The establishment of the model improves the early screening of patients with MCRC. Conclusion: Patients with colorectal cancer and high expression of FR+CTC and HSP90 are at risk of liver metastasis and this suggests a poor prognosis. Combining the two markers can improve the early screening and diagnosis of LMCRC patients. In addition, combining a multivariate risk model can further assist patients in appropriate stratification and the design of tailored treatment regimens. However, further validation these markers is needed before their routine clinical application.

Preoperative Neutrophil-BMI Ratio As a Promising New Marker for Predicting Tumor Outcomes in Colorectal Cancer.

Background: Inflammation and nutritional status are highly associated with colorectal cancer (CRC) prognosis. This study aimed to evaluate the prognostic value of the preoperative neutrophil-BMI ratio (NBR) in patients with CRC. Methods: A retrospective analysis was performed on 2471 patients with CRC who underwent surgical resection between 2004 and 2019. Patients were divided into two groups based on the cutoff value for NBR. Cox regression and Kaplan-Meier curves were used to evaluate overall survival (OS). Results: High NBR was associated with female sex, low BMI, colon, right-sided CRC, poor differentiation, T3 to 4 stage, M1 to 2 stage, high carcinoembryonic antigen (CEA) level, III-IV stage, microsatellite instability (MSI), and no adjuvant chemotherapy (all P < .05). The high NBR group had a shorter OS than the low NBR group. Female and right sided patients with CRC and with high NBR had a worse prognosis. Univariate Cox regression suggested that NBR was significantly associated with poor prognosis. Multivariate analysis confirmed that age (P = .019,HR:1.012), differentiation (P = .001,HR:1.306), TNM stage (P < .001,HR:2.432), CEA (P = .014,HR:1.001), and NBR (P < .001, HR: 3.309) were independent poor prognostic factors for OS. Subgroup univariate analysis indicated that female patients with high NBR had a worse prognosis. A nomogram composed of TNM stage, CEA, and NBR was developed, and internal validation was based on female patients with CRC. The nomogram provided good discrimination for both the training and validation sets, with area under the curve values of 0.79 and 0.769, respectively. Conclusions: High preoperative levels of NBR are indicators of poor prognosis in patients with CRC.

Proteomics and liquid biopsy characterization of human EMT-related metastasis in colorectal cancer.

Tumor cells undergo epithelial-mesenchymal transition (EMT), however, there is a room of disagreement in role of EMT heterogeneity to colorectal cancer metastasis (mCRC) evolution. To uncover new EMT-related metastasis proteins and pathways, we addressed the EMT status in colorectal cancer liver metastasis patient-derived CTCs to identify proteins that promote their distant metastasis. And then, we performed a comparative proteomic analysis in matched pairs of primary tumor tissues, adjacent mucosa tissues and liver metastatic tissues. By integrative analysis we show that, unstable Epithelial/Mesenchymal (E/M)-type CTCs had the strongest liver metastases formation ability and the proportion of E/M-type CTCs correlated with distant metastases. Using an optimized proteomic workflow including data independent acquisition (DIA) and parallel reaction monitoring (PRM), we identified novel EMT-related protein cluster (GNG2, COL6A1, COL6A2, DCN, COL6A3, LAMB2, TNXB, CAVIN1) and well-described (ERBB2) core protein level changes in EMT-related metastasis progression, and the proteomic data indicate ERBB2, COL6A1 and CAVIN1 are promising EMT-related metastatic biomarker candidates. This study contributes to our understanding of the role that EMT plays in CRC metastasis and identifies heterogeneous EMT phenotypes as a key piece for tumor progression and prognosis. We further propose that therapies targeting this aggressive subset (E/M-type) of CTCs and related protein may be worthy of exploration as potential suppressors of metastatic evolution.

Adjuvant imatinib for gastrointestinal stromal tumors: the current situation and problems.

OBJECTIVE: To review the current situation and find out the current problems of adjuvant imatinib for gastrointestinal stromal tumors (GISTs). METHODS: Searching for articles and records about imatinib for GISTs, especially adjuvant imatinib for GISTs, on MEDLINE, EMBASE and international conference on gastrointestinal. RESULTS: GISTs are derived from mesenchymal cells of the gastrointestinal tract. The standard treatment for primary GISTs is to resect the tumor together with the negative margins completely without tumor rupture and spillage. Conventional chemotherapy and radiotherapy is ineffective for advanced GISTs. The introduction of imatinib has dramatically changed the natural history of advanced GISTs. Imatinib is generally safe and effective with doses of 400, 600 or 800 mg daily, and has become the standard drug in the treatment for patients with advanced GISTs. Furthermore, most of the toxicity of imatinib is minimal and manageable, almost no treatment-related deaths have been reported. Therefore, adjuvant imatinib therapy is safe and seems to improve recurrence-free survival after the resection of primary GISTs. CONCLUSIONS: Although U.S Food and Drug Administration and European Medicines Agency have approved the use of adjuvant imatinib for GISTs postoperatively, a series of questions about the use of adjuvant imatinib still exist, such as the impact of adjuvant imatinib on overall survival, the optimal dose, the best duration of treatment and the most suitable patients. Doctors and patients should weigh the pros (the decrease of relapse) and cons (drug toxicity and drug costs), especially in terms of the benefit of overall survival.

Immune infiltration and immune gene signature predict the response to fluoropyrimidine-based chemotherapy in colorectal cancer patients.

Fluoropyrimidine-based chemotherapy is an essential component of systemic chemotherapy for colorectal cancer (CRC). The immune response is implicated in chemotherapy-induced cytotoxicity. Here, we reported an immune risk (Imm-R) model for prognostic prediction in patients receiving fluoropyrimidine-based chemotherapy. Gene expression profiles and corresponding clinical information were collected from four data sets and divided into training set (n = 183) and validation set (validation set1: n = 34; validation set2: n = 99). The composition of 22 tumor-infiltrating immune cells (TIICs) populations was characterized with the CIBERSORT deconvolution algorithm. A prognostic Imm-R model for predicting overall survival was established by performing least absolute shrinkage and selection operator (LASSO) penalized COX regression analysis. T follicular helper cells and M0 macrophages were associated with better survival, while eosinophils were associated with worse survival. TIICs signature was constructed based on the above three immune cell types. Furthermore, a Imm-R model was created by integrating TIICs signature with immune-related genes (IRGs), which effectively in distinguishing CRC patients with poorer prognosis. The Imm-R model was associated with activation of the TGF-beta signaling and suppression of DNA damage. Results of this research provide new insights into the role of immunity for in fluoropyrimidine-based chemotherapy as well as a useful tools to predict the outcome of CRC patients receiving fluoropyrimidine-based chemotherapy.

Comparative study of clinical efficacy using three-dimensional and two-dimensional laparoscopies in the treatment of distal gastric cancer.

BACKGROUND: Three-dimensional (3D) laparoscopy has the advantages and characteristics of more radical procedures in the treatment of gastric cancer. The objective of this research was to investigate the short-term efficacy and safety of 3D laparoscopic procedures in the treatment of advanced distal gastric cancer. METHODS: We retrospectively analyzed the clinical data of 124 patients treated with 3D and two-dimensional (2D) laparoscopic D2 lymphadenectomy for distal gastric cancer at the China Academy of Medical Sciences Cancer Hospital and the Affiliated Cancer Hospital of Guangxi Medical University from January 2014 to January 2015. The effects on operative time, bleeding, hospitalization time, complications, and the number of lymph nodes removed were analyzed. RESULTS: The difference between the general data of the two groups was not statistically significant (P>0.05). In analysis of the subgroups, the number of lymph nodes removed in the 3D laparoscopic group was significantly higher than in the 2D laparoscopic group ([2.52±1.88] vs [2.22±1.80], P=0.001; [2.22±1.80] vs [1.47±1.99], P=0.019). However, the differences among the total number of lymph nodes removed, operative time, intraoperative blood loss, intraoperative complications, postoperative complications, postoperative recovery time, and postoperative hospital stay were not statistically significant. CONCLUSION: 3D laparoscopic-assisted radical gastrectomy for distal advanced gastric cancer is safe and feasible.

Primary hepatic non-Hodgkin's lymphoma with rectal cancer: A case report.

Primary hepatic non-Hodgkin's lymphoma (NHL) is an extremely rare disease that is commonly neglected as a possible diagnosis. The present study reports the case of a middle-aged male with chronic hepatitis B in which primary hepatic NHL and rectal cancer occurred simultaneously. A large solitary tumor in the left lobe of the liver was incidentally detected on routine examination prior to the laparoscopic resection of the rectal cancer. Laparoscopic resection of the rectal cancer and a liver biopsy were performed simultaneously. The pathology revealed that the hepatic tumor was NHL and that the rectal cancer was adenocarcinoma. Systemic staging revealed no evidence of nodal or bone marrow involvement, therefore, primary hepatic lymphoma (PHL) was diagnosed. PHL associated with rectal adenocarcinoma is extremely rare and to the best of our knowledge, has never been reported. At present, the cause and most effective therapy for the condition remain unclear.