Deficiency of SDHC promotes metastasis by reprogramming fatty acid metabolism in colorectal cancer.

BACKGROUND: Several studies have demonstrated a strong correlation between impaired Succinate dehydrogenase (SDH) function and the advancement of tumors. As a subunit of SDH, succinate dehydrogenase complex subunit C (SDHC) has been revealed to play tumor suppressive roles in several cancers, while its specific role in colorectal cancer (CRC) still needs further investigation. METHODS: Online database were utilized to investigate the expression of SDHC in colorectal cancer and to assess its correlation with patient prognosis. Cell metastasis was assessed using transwell and wound healing assays, while tumor metastasis was studied in a nude mice model in vivo. Drug screening and RNA sequencing were carried out to reveal the tumor suppressor mechanism of SDHC. Triglycerides, neutral lipids and fatty acid oxidation were measured using the Triglyceride Assay Kit, BODIPY 493/503 and Colorimetric Fatty Acid Oxidation Rate Assay Kit, respectively. The expression levels of enzymes involved in fatty acid metabolism and the PI3K/AKT signaling pathway were determined by quantitative real-time PCR and western blot. RESULTS: Downregulation of SDHC was found to be closely associated with a poor prognosis in CRC. SDHC knockdown promoted CRC metastasis both in vitro and in vivo. Through drug screening and Gene set enrichment analysis, it was discovered that SDHC downregulation was positively associated with the fatty acid metabolism pathways significantly. The effects of SDHC silencing on metastasis were reversed when fatty acid synthesis was blocked. Subsequent experiments revealed that SDHC silencing activated the PI3K/AKT signaling axis, leading to lipid accumulation by upregulating the expression of aldehyde dehydrogenase 3 family member A2 (ALDH3A2) and reduction of fatty acid oxidation rate by suppressing the expression of acyl-coenzyme A oxidase 1 (ACOX1) and carnitine palmitoyltransferase 1A (CPT1A). CONCLUSIONS: SDHC deficiency could potentially enhance CRC metastasis by modulating the PI3K/AKT pathways and reprogramming lipid metabolism.

Matrix Metalloproteinase 11 Promotes Migration and Invasion of Colorectal Cancer by Elevating Slug Protein.

Purpose: Matrix metalloproteinase-11 (MMP11), which belongs to the stromelysin subgroup, has been reported to play a role in the progression of colorectal cancer (CRC). However, the significance of MMP11 in the tumor microenvironment, immune/stromal cells, and its mechanism in CRC remain unclear. Methods: The impact of MMP11 knockdown using specific short hairpin RNAs (shRNAs) on the metastasis and invasion of colorectal cancer RKO and SW480 cells was investigated using western blot, quantitative real-time polymerase chain reaction (qRT-PCR), transwell assays, and immunohistochemistry. Results: MMP11 mRNA expression was significantly higher in CRC cells than in normal cells, and its expression was stimulated in CCD-18Co fibroblasts. Additionally, MMP11 expression was found to be higher in individuals aged ≤ 65 years, the T4/T3 group, and Stage III/IV patients. Overall survival (OS) and disease-free survival rates were significantly different between the high and low MMP11 groups. Furthermore, the receiver operating characteristic (ROC) curves for MMP11 at 1-, 3-, and 5-years were 0.450, 0.552, and 0.560, respectively. Moreover, MMP11 promoted the migration and invasion of CRC cells by elevating the expression of Slug protein. Most importantly, MMP11 was positively associated with M0-macrophages and negatively associated with M1-macrophages, NK cells activated, NK cells resting, T cells CD4 memory activated, and T cells follicular helper, indicating the remarkable interactions of MMP11 with tumor immunology. Conclusions: MMP11 plays an important role in colorectal cancer development, and its mechanism in CRC needs to be further explored in the future.

[Correlation between serum iron level and overall survival of oral cancer].

OBJECTIVE: To explore the correlation between serum iron(Fe) and the overall survival of oral cancer. METHODS: Patients with oral cancer who met the inclusion criteria in the Department of Oral and Maxillofacial Surgery of the First Affiliated Hospital of Fujian Medical University from January 2010 to April 2017 were collected. The average age was(57.12±13.94) years old, including 489 males(65.46%), 258 females(34.54%) and 564 cases of squamous cell carcinoma(77.90%). Overall survival rates were calculated by Kaplan-Meier method. Survival difference was compared by log-rank test. Cox regression model was used to estimate the hazard ratio(HRs) and 95% confidence intervals(95%CIs). RESULTS: The distributions of serum iron level were non-normal distribution(P<0.001), and the serum iron level is expressed as 13.9(10.3, 17.8)µmol/L in M(P25, P75). According to X-tile, the optimal cut-off value of serum iron was 15.3 µmol/L, used as a criterion to group patients. The result showed that the mortality risk of patients with oral cancer in high serum iron level(Fe>15.3 µmol/L) was 0.72 times of patients in lower one(Fe≤15.3 µmol/L)(95%CI 0.52-0.99). Stratified analysis suggested that serum iron was a good predictor of patients with oral cancer aged 60 years(HR=0.62, 95%CI 0.39-0.99), male(HR=0.66, 95%CI 0.44-0.98), with TNM stage I-II(HR=0.42, 95%CI 0.20-0.88) and squamous cell of pathological type(HR=0.69, 95%CI 0.49-0.97). CONCLUSION: Serum iron is closely related to the overall survival of oral cancer, patients with high serum iron have a lower risk of death.

Knowledge mapping of metformin use on cancers: a bibliometric analysis (2013-2023).

There is substantial evidence from clinical and preclinical studies suggesting an association between metformin use and a reduced risk of cancer. However, the effects of metformin use on cancers have not yet been subjected to bibliometric analysis. The goal of this study was to explore the potential effects of metformin use on cancers and to conduct a comprehensive assessment of research hotspots related to the use of metformin on cancers. The results of the literature analysis were visualized using various tools such as Adobe Illustrator CC 2018, VOSviewer, CiteSpace, and the R package "bibliometric." The average annual publications from 2013 to 2023 was 372. In terms of journals and co-cited journals, a total of 1,064 journals published 1958 papers, and Oncotarget published the highest number of papers (n = 153, 7.81%), while Cancer Research (Co-citation = 5,125) was the most frequently cited journal. A total of 25,665 authors participated in the research on metformin use on cancers. Metformin has demonstrated improved outcomes in various types of cancer, including breast cancer (BC), lung cancer (LC), colorectal cancer (CRC), prostate cancer (PC), and pancreatic cancer. This bibliometric analysis reviews the current literature on the clinical data on metformin use on cancers and describes the preclinical evidence illustrating the potential mechanisms of metformin use on various cancers directly or indirectly.