Colorectal cancer is a common cancer worldwide, and distant metastasis is a key factor in its death, so it is crucial to study the mechanism of distant metastasis of colorectal cancer and find new treatment options. Succinate was found to be a tumor source of a new class of cancer progression factors[13–14]. An increasing number of studies have proven that succinate is abnormal in a variety of tumors, including ovarian cancer, lung cancer and gastric cancer, and promotes the development of tumors through various mechanisms, which may be related to tumor immunity, oxidative stress, cellular metabolism and the inflammatory response[6, 15, 16]. However, there is no evidence for a role of succinate in colorectal cancer. This study found that succinate could significantly enhance the metastasis and invasion of HCT116 and SW480 cells and enhance p-STAT3 expression and the EMT process.
In the tumor microenvironment, cancer cells release signaling molecules to activate their own oncogenic signals to change the surrounding cells and the environment to promote tumor progression. Alterations in cell metabolism have been recognized as markers of cancer cells, providing new potential targets in terms of tumor therapy. Specific metabolites can maintain normal physiological processes, and abnormal metabolite accumulation plays a key role in promoting the progression of the disease. The inflammatory microenvironment of tumors is composed of a large number of cytokines and various proteolytic enzymes involved in the inflammatory response, which change the cellular environment and induce the inflammatory cancer transformation of normal cells[17–18]. The role of succinate in addition to metabolism is gradually being evaluated. This molecule also acts as a signal of inflammation to promote macrophage inflammatory factor IL-1 β production and increase fibroblast IL-6 production by stabilizing HIF-1α[19–20]. Increased succinate was found in both the feces of mice with IBD and humans and was shown to be associated with disease activity[21]. Metagenomic studies of the gut microbiome of IBD patients found significantly lower levels of specific succinate-consuming bacterial strains[22–23]. All of these findings suggest that succinate plays an important role in the intestinal inflammatory response, and the inflammatory response is an important factor in the development of colorectal cancer. However, the role of succinate in colorectal cancer has not been proven. We detected the levels of succinate in cancer tissues and adjacent tissues of colorectal cancer patients undergoing radical resection and found that the levels of succinate in colorectal cancer tissues were significantly higher than those in adjacent normal tissues, further confirming that succinate may play an important role in the development of colorectal cancer. Unfortunately, we did not further determine whether succinate accumulates in the cytosol or extracellular space.
The STAT family includes multiple activators of signal transduction and transcription, in which STAT3 is involved in multiple biological processes, including cell survival, proliferation, differentiation, tumorigenesis and angiogenesis[24–25]. Under certain stimulation conditions, the STAT3 pathway is hyperactivated by high levels of IL-6 through direct phosphorylation of tyrosine and serine residues[26]. STAT3 activation has important effects on both cell growth and apoptosis and the regulation of the cell cycle. Multiple studies have confirmed that STAT3 is hyperactivated in most human cancers, is activated in many solid and hematological tumors and is associated with poor clinical outcomes[27]. Studies have reported that STAT3 overexpression plays a crucial pathogenic role in the development, progression and metastasis of colorectal cancer[28]. As an upstream mediator of EMT, STAT3 can upregulate EMT expression in brain tumors, lung cancer and gastrointestinal cancer to mediate tumor metastasis and plays an important role in the development of various tumors[29]. During EMT, epithelial-derived tumor cells lose cell polarity, intercellular junctions become loose, and the cytoskeleton reorganizes, resulting in decreased adhesion of tumor cells, which significantly enhances the migration and invasion of cells. During the development of EMT, the expression level of E-cadherin (E-cadherin), which is an epithelial indicator, decreased, and the expression of mesenchymal cell characteristic molecules (such as N-cadherin and Vimentin) increased, which is considered to be a key step in the migration and metastasis of tumor cells[30]. To verify the effect of succinate on colorectal cancer migration and invasion, we confirmed that the migration, invasion and EMT processes were strengthened after succinate treatment. In addition, we used a STAT3 inhibitor to study succinate-driven STAT3 phosphorylation to affect tumor migration, and our results showed that when the colorectal cancer cell lines SW480 and HCT116 were treated with the STAT3 inhibitor HO-3867, the migration, invasion and EMT processes were weakened. In vivo experiments further confirmed that succinate can increase STAT3 phosphorylation expression and strengthen the EMT process, consistent with in vivo experiments, but unfortunately, we did not further verify whether succinate still promotes tumor metastasis after interfering with STAT3 phosphorylation in vivo.
In conclusion, succinate promotes the metastasis and invasion of colorectal cancer, and when cancer cells are specifically inhibited by a STAT3 inhibitor, the effect of succinate in promoting cancer cell metastasis and invasion is weakened. This process may be associated with succinate activation of STAT3, which upregulates EMT-related expression and subsequently promotes distant metastasis in colorectal cancer. These findings have potential clinical implications and provide an important reference for the treatment and prognosis of colorectal cancer patients. However, the specific mechanism of the excessive accumulation and secretion of succinate in tumors and in vivo experiments need to be further explored.