Exploiting branched-chain amino acid metabolism and NOTCH3 expression to predict and target colorectal cancer progression.

Background: The interplay between colon adenocarcinoma (COAD) and branched-chain amino acid (BCAA) metabolism is not fully understood, presenting a crucial area for investigation. Methods: We developed a prognostic model based on BCAA metabolism using the least absolute shrinkage and selection operator (LASSO) regression algorithm. We employed qRT-PCR and Western blot analyses to examine NOTCH3 expression in COAD tissues versus adjacent non-cancerous tissues and various cell lines. We also investigated the impact of NOTCH3 on COAD cell proliferation, invasion, and migration through in vitro and in vivo experiments. Results: Our BCAA metabolism-related signature (BRS) distinguished between different immune features, tumor mutation burdens, responses to immunotherapy, and drug sensitivity among COAD patients. NOTCH3 was found to be overexpressed in COAD, promoting tumor growth as verified through various assays. The model effectively predicted COAD prognosis and patient responses to treatments, underscoring the potential of BCAA pathways as therapeutic targets. Conclusion: The BRS is instrumental in predicting the prognosis and therapeutic response in COAD, with NOTCH3 playing a significant role in the proliferation, invasion and migration of COAD. These findings suggest that targeting BCAA metabolism and NOTCH3 could advance COAD treatment strategies.

A thirty-three gene-based signature predicts lymph node metastasis and prognosis in patients with gastric cancer.

Recently, several studies have indicated the great potential of gene expression signature of the primary tumor in predicting lymph node metastasis; however, few current gene biomarkers can predict lymph node status and prognosis in gastric cancer (GC). Thus, we used the RNA-seq data from The Cancer Genome Atlas (TCGA) to identify differentially expressed genes between pathological lymph node-negative (pN0) and positive (pN+) patients and to establish a gene signature that could predict lymph node metastasis. Meanwhile, the robustness of identified gene signatures was validated in an independent dataset Asian Cancer Research Group (n = 300). In this study, our thirty-three gene-based signature was highly correlated with lymph node metastasis and could successfully discriminate pN + patients in the training set (Area under the receiver operating characteristic curve = 0.951). Moreover, Disease-free survival (P = 0.0029) and overall survival (P = 0.026) were significantly worse in high-risk compared with low-risk patients overall and when confined to pN0 patients only (P < 0.0001). Of note, this gene signature also proved useful in predicting lymph node status and survival in the validation cohort. The present study suggests a thirty-three gene-based signature that could effectively predict lymph node metastasis and prognosis in GC.

Expression of FOXA1 gene regulates the proliferation and invasion of human gastric cancer cells.

Forkhead box (FOX) transcription factors regulate the development of several human cancers. However, the role and therapeutic potential of FOXA1 in gastric cancer is still largely unexplored. The results showed a significant (P < 0.05) upregulation of FOXA1 in gastric cancer tissues and cell lines. Silencing of FOXA1 in gastric cells significantly (P < 0.05) decreased their viability through induction of apoptosis. The induction of apoptosis was associated with upregulation of Bax and downregulation of Bcl-2. Additionally, FOXA1 silencing caused activation of caspase-3 and 9 with no apparent effects on the expression of caspase-8 suggestive of intrinsic apoptosis. The transwell cell invasion revealed significant (P < 0.05) decline of cell invasion of gastric cancer cells upon FOXA1 silencing. The FOXA1 knockdown further inhibited the in vivo tumor growth suggestive of its therapeutic potential. Taken together, the findings of the present revealed that FOXA1 regulates the proliferation and development of gastric cancer and may exhibit therapeutic implications in gastric cancer treatment.

Hyperuricemia is a Adverse Prognostic Factor for Colon Cancer Patients.

OBJECTIVE: Hyperuricemia is linked to the prognosis of a number of cancers; however, its association with colon cancer survival has not been fully elucidated. To investigate whether hyperuricemia affects the prognosis of colon cancer, we conducted a retrospective study. METHODS: The study included age- and sex-matched colon cancer patients, of whom 60 patients were diagnosed with hyperuricemia, and 120 patients did not have hyperuricemia. The overall survival (OS) and disease-free survival (DFS) of these patients were evaluated by Kaplan-Meier (K-M) analysis. The association between the survival of colon cancer patients and hyperuricemia was analyzed using the Cox regression method after adjusting for tumor stage and grade and vascular infiltration. RESULTS: The K-M survival analysis supported that patients with hyperuricemia had poor OS (P for the Log rank test = 0.0008) and DFS. As demonstrated by the univariate analysis, the presence of hyperuricemia was correlated with decreased OS (HROS = 2.09, P = 0.002). Tumor grade and tumor stage were also found to be independent predictors for the prognosis of colon cancer patients. In addition, poor OS among patients with hyperuricemia was also confirmed in the adjusted analysis (HROS = 1.94, P = 0.005). CONCLUSION: Hyperuricemia has an adverse effect on the prognosis and survival of patients with colon cancer. Further studies evaluating the cellular and molecular mechanisms are needed to validate the prognostic value of hyperuricemia in colon cancer.

Genetic polymorphisms of Cathepsin B are associated with gastric cancer risk and prognosis in a Chinese population.

BACKGROUND: Genetic polymorphisms are believed to represent a key aspect of predisposition to gastric cancer (GC). Therefore, considering the important role of Cathepsin B (CTSB) in promoting cancer onset and development, it could be very worthful to explore the function of CTSB-related genetic polymorphisms in GC. OBJECTIVE: In this study, we investigated the correlation of CTSB-related polymorphisms (rs9009A>T, rs6731T>C, rs1293303G>C, rs1874547C>T, rs3779659C>T, rs17814426C>T and rs148669985C>T) with GC risk and prognosis in a case-control study of 994 cases and 1000 controls. METHODS: All tag single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction-ligase detection reaction (PCR-LDR) sequencing technology. RESULTS: The results indicated rs9009, rs6731 and rs17814426 correlated with decreased risks of GC (HR = 0.97, p< 0.001; HR = 0.86, P= 0.019; HR = 0.85, P= 0.017; respectively). Stratification analysis further showed rs17814426 variant genotypes correlated with earlier T stage (p= 0.044). In addition, GC patients carrying the C allele of rs6371 had better overall prognosis (HR = 0.62, 95%CI = 0.44-0.88). CONCLUSION: Our results firstly suggested the importance of CTSB-related polymorphisms on GC which could predict GC risk and prognosis.

Correlations of SNHG5 genetic polymorphisms with susceptibility and prognosis to gastric cancer in a Chinese population.

The most studied genetic polymorphisms associated with gastric cancer (GC) risk are located in protein-coding genes. However, these sited in long noncoding RNA (lncRNA) are not adequately explored yet. Here, we designed a case-control study of 848 cases and 880 controls to investigate the associations of polymorphisms (rs61396151, rs1059307, rs11961028, rs9351065) in lncRNA SNHG5 with the risk and prognosis of GC. The results indicate rs61396151 associated with decreased risk of GC (OR = 0.78, 95% CI = 0.62-0.96), but there were no correlations observed with the clinicopathological features of GC (P > 0.05). However, the CA genotype of rs61396151 was correlated with poor overall survival rate in a multivariate cox regression model (HR = 1.91, P = 0.040), but it was reversed with adjustment for age, gender and TNM stage (HR = 1.35, P = 0.213). Collectively, our results highlight the importance of SNHG5-related polymorphisms to GC susceptibility and prognosis.

The Role of Tumor Deposits in Predicting the Efficacy of Chemotherapy in Stage III Colon Cancer.

PURPOSE: To evaluate the role of tumor deposits (TDs) in predicting the efficacy of chemotherapy in stage III colon cancer. METHODS: Using the SEER∗Stat software Version 8.3.6, we started with a national cohort of colon cancer cases diagnosed between 2004 and 2016. We used the χ2 (Chi-square) test to compare differences between different categorical variables according to the number of TDs. The Cox proportional hazards regression model was used to determine the independent association of different clinical and pathological variables with CSS, which were adjusted for other significant prognostic factors. RESULTS: We have identified 29,017 patients diagnosed with stage III colon cancer from the SEER database. The results of multivariate analyses showed that patients with the receipt of chemotherapy had 54.7% decreased risk of cancer-specific mortality compared with those not (HR = 0.453, 95% CI = 0.425-0.483, P < 0.0001) in the no-TD group; In the 1-2-TD group, patients with the receipt of chemotherapy had 56.8% decreased risk of cancer-specific mortality compared with those not (HR = 0.432, 95% CI = 0.364-0.512, P < 0.0001); In the ≥3-TD group, patients with the receipt of chemotherapy had 51.8% decreased risk of cancer-specific mortality compared with those not (HR = 0.482, 95% CI = 0.389-0.597, P < 0.0001). CONCLUSIONS: Our study demonstrated that the presence of TDs was associated with a dismal prognosis and high number of TDs would also contribute to the worse survival of colon cancer. High number of TDs did not affect the survival benefit of chemotherapy in stage III colon cancer.