Colorectal cancer is the second most common cause of cancer deaths worldwide and is expected to cause 1.2 million deaths by 2030 (21, 22). Considering that most patients with colorectal cancer progress slowly over many years, colorectal cancer is usually curable if diagnosed at an early stage (23). Screening for colorectal cancer requires the development of sensitive biomarkers in peripheral blood. Many members of the TRIM protein family have been reported to act as oncogenic and tumor-suppressive factors in gastrointestinal cancers via different signaling pathways (24). In addition, TRIM47 may be an effective diagnostic marker for predicting colorectal cancer (25).

The gene and protein levels of MG53 were considerably lower in colon cancer tissues than in healthy colon tissues, and the same results were found in the serum of patients with colon cancer (26). In colon cancer and normal colon tissues, MG53 may be expressed and secreted by stromal cells instead of normal colon or colon cancer cells, and serum MG53 levels are negatively correlated with colon cancer stage and metastasis, suggesting that the low MG53 levels in the serum of patients with colon cancer may be due to local tissue lesions (26). Low levels of MG53 in focal tissues have also been suggested to account for the poor prognosis of stage II colon carcinoma (27). Under colorectal carcinogen induction, MG53 knockout mice present more severe tumor progression than wild-type mice, whereas mice with MG53 overexpression have relatively good colorectal structure and function (19). MG53 has also been shown to inhibit the proliferation of colorectal cancer cells in an in vitro study. And this study found that MG53, as an E3 ubiquitin ligase capable of targeting cyclin D1, induces its ubiquitination-dependent degradation to inhibit the proliferation of gastrointestinal cancer cells by arresting the cell cycle at the G1 phase (28). In addition, MG53 acts differently on different anticancer drugs. MG53 and pabocinib inhibit the proliferation of colon cancer cells synergistically, and MG53 could partially ameliorate drug resistance (19). The safety of recombinant human MG53 (rhMG53) has been validated in a mouse model of colorectal cancer (28). Although rhMG53 do not affect the doxorubicin sensitivity of resistant colorectal cancer cells (SW620/AD300), it inhibits the proliferation of colorectal cancer cells. Moreover, in mouse tumor xenograft models of colorectal adenocarcinoma with multidrug resistance, the combination of doxorubicin and rhMG53 appeared to be more effective than doxorubicin or rhMG53 alone (28).

Although vaccination and antiviral therapy have reduced the incidence of hepatocellular carcinoma, the incidence and mortality rates of this malignancy continue to increase in many regions of the world (29). In hepatocellular carcinoma, the expression of numerous TRIM proteins tends to be altered and has been shown to be correlated with diagnosis, treatment, and prognosis (30). TRIM proteins appear to be involved in the survival, growth, aerobic glycolysis, immune infiltration, and invasion of hepatocellular carcinoma cells (31–34).

The mRNA expression of MG53 was detected in human hepatocellular carcinoma and normal human hepatocyte cell lines. In patients with hepatocellular carcinoma, the high expression of MG53 may be associated with poor overall survival (35). However, one study has shown that the gene and protein expression levels of MG53 have been suggested to be drastically lower in hepatocellular carcinoma tissue than in matched noncancerous liver tissue (17). MG53 regulates the ubiquitination and degradation of RAC1, a small GTPase with oncogenic function, this effect, in turn, inhibits the malignant progression of hepatocellular carcinoma and improves the resistance of hepatocellular carcinoma to sorafenib treatment by blocking the RAC1/MAPK signaling pathway (17).

Although the application of precision medicine in NSCLC treatment has advanced considerably over the past decade, the 5-year survival rate of patients with metastatic NSCLC remains less than 5% due to multiple drug resistance mechanisms (36, 37). Some TRIM proteins may contribute to NSCLC or resistance to targeted drugs (38–44), whereas others have completely opposite functions (45–47).

MG53 is downregulated in metastatic tumors from patients with NSCLC relative to in nonmetastatic tumors, and MG53 knockout promotes the growth and metastasis of lung tumors in mice (48, 49). G3BP2, a protein associated with the formation of multiple tumors, was upregulated in the cytosol of tumor cells from patients with NSCLC relative to in nontumor cells. Circulating levels of MG53 appear to influence the proliferation and migration of NSCLC cells directly via G3BP2. Instead of performing classical ubiquitination-dependent degradation functions, the amino terminus of MG53 physically interacts with G3BP2 and enhances its nuclear translocation, which may be a key mechanism by which MG53 inhibits the G3BP2-mediated formation of lung cancer tumors and stress granules (20, 50). Furthermore, an in vitro study showed that rhMG53 inhibited the formation of stress granules and potentiated the cytotoxic effect of cisplatin on human NSCLC cells (20).

MG53 appears to have an ameliorative effect on multiple types of cancer. However, many TRIM proteins have inconsistent effects on different cancers. A three-dimensional growth system study reported that MG53 dramatically suppressed the proliferation, invasion, and colony formation of tongue cancer cells (18). Knocking down MG53 in tongue cancer cells resulted in a remarkable increase in the phosphorylation of AKT^Ser308 and AKT^Thr473. Animal studies showed that in mice, knocking out MG53 also accelerated the progression of tongue cancer (18). O6-methylguanine DNA methyl transferase (MGMT) is an important target in cancer therapy because it blocks the beneficial effects of chemotherapy on tumor cells (51). The RING structural domain of MG53 interacts with the N-terminal region of MGMT and regulates the ubiquitination-dependent degradation of MGMT. Human uveal melanoma cells have higher MGMT levels and lower MG53 levels than normal human pigment epithelium cells. MG53 overexpression in uveal melanoma cells contributes to improved chemoresistance to dacarbazine treatment (52). MG53 is downregulated in the tumor tissue of patients with breast cancer relative to in paired adjacent nontumor tissue and is also downregulated in many breast cancer cell lines relative to in normal human mammary cell lines. In vivo and in vitro, MG53 inhibits breast cancer progression likely because it can inhibit the activation of the PI3K/Akt/mTOR pathway and reduce lactate levels through protein phosphatase 3 catalytic subunit α (53). One study analyzed ubiquitin-related genes in The Cancer Genome Atlas cohort and found that MG53 was correlated strongly with the grade, stage, and T stage of clear cell renal cell carcinoma. However, the expression of MG53 in patients with clear cell renal cell carcinoma remains to be confirmed (54).

In accordance with the current evidence, MG53 appears to be beneficial for delaying the progression of various cancers and improving resistance to some anticancer drugs in in vitro and animal models ( Figure 1 ). Available studies suggest that the antitumor effect of MG53 may be mainly derived from its role as an E3 ubiquitin ligase. However, the current evidence for specific cancer types remains insufficient and lacks mechanism research. Further safety verification is required for the application of rhMG53.

During cancer progression and treatment, many organs suffer varying degrees of tissue damage from the tumor, cancer complications, and treatment side effects, all of which are related to plasma membrane damage and may accelerate cancer progression (55–57). MG53 was initially well known for its function in the repair of muscle cell membranes. Evidence showing that MG53 can participate in the repair of various cell membranes and promote tissue regeneration has emerged with the deepening of research (13, 58). MG53 secreted by skeletal muscles is transported in the circulatory system in the form of vesicles and participates in muscle cell membrane repair. The failure of MG53-mediated membrane damage repair may cause certain skeletal muscle diseases (12, 59–61). In addition, the pathological processes of myocardial injury and cancer are intertwined, and heart failure induced by anticancer therapy has become a key focus in cardiac oncology research (62, 63). Evidence also suggests that cancer and ischemia–reperfusion injury share common pathways also exists (64).

Inflammatory response is an important defense mechanism of the body, but it can also promote the formation of tumor microenvironment and tumor promotion, especially chronic inflammation (99). Anti-inflammatory therapy targeting inflammation-related factors such as nuclear factor-κB (NF-κB) plays an important role in cancer control (100). TRIM proteins are widely involved in regulating inflammatory responses and MG53 appears to have anti-inflammatory effects in multiple tissues (101).

MG53 interacts with the p65 subunit of NF-κB and thereby inhibits the nuclear translocation of NF-κB, which in turn alleviates inflammatory responses in kidney, nervous system and airway (70, 102, 103). After infection of macrophages or mice with virus, MG53 attenuates inflammatory response by decreasing type I interferon levels (104). In mice with Duchenne muscular dystrophy, MG53 appears to enhance mitochondrial autophagy, thereby reducing nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasomes and suppressing chronic inflammation in skeletal muscles (105). Similarly, it was emphasised that MG53 may improve neuroinflammation by decreasing NLRP3 inflammasomes in a study using human umbilical cord mesenchymal stem cells and mice (106).

MG53 can ameliorate inflammation in many disease models, but its role in carcinogenic inflammation, inflammation caused by cancer and inflammation triggered by cancer treatment remains to be investigated.

Furthermore, other biological functions of MG53 may be beneficial for cancer therapy. For example, angiogenesis is an important target for cancer treatment, and MG53 inhibits angiogenesis in vivo and in vitro by decreasing focal adhesion kinase phosphorylation and blocking the Src/Akt/ERK1/2 signaling pathway (107, 108). Peroxisome proliferator-activated receptor-α (PPARα) agonists have a role in anti-tumor therapy and MG53 attenuates inflammatory responses in cardiomyocytes by upregulating PPARα expression (109, 110). However, there is too little relevant evidence to demonstrate that these functions of MG53 are beneficial for cancer therapy.

Insulin resistance is a key factor in the occurrence and development of cancer, and a substantial proportion of patients with cancer have insulin resistance (111–114). Impaired glucose tolerance is also strongly associated with long-term cancer risk and is an important risk factor for cancer-related death (115–119). During cancer treatment, the blood glucose and insulin levels of patients must be monitored to learn about the insulin resistance induced by therapeutic measures and thus adjust the treatment protocol promptly (120).

The relationship between MG53 and insulin resistance has long been controversial. Some studies have suggested that MG53 induces insulin resistance through multiple pathways, including targeting insulin receptor substrate 1 (IRS-1), insulin receptors (IRs), and AMP-activated protein kinase for ubiquitin-dependent degradation, promoting the expression of peroxisome proliferator-activated receptor-α and its target genes to facilitate myocardial lipid uptake and thereby leading to lipid accumulation and toxicity, and binding to the extracellular structural domains of IRs to inhibit receptors allosterically (15, 121–124). In addition, the direct application of rhMG53 may exacerbate insulin resistance, and the protective effect of MG53 on myocardial cells may be counteracted by its adverse metabolism. Two mutants of rhMG53, rhMG53-C14A and rhMG53-S255A, can eliminate adverse effects on metabolism while retaining the membrane repair function of rhMG53 (121, 125–128).

However, MG53 expression is inconsistent in various models of metabolic disorders, and neither the ablation nor overexpression of MG53 in wild-type and db/db mice has been noted to alter insulin signaling. Additionally, in rats, the repeated intravenous administration of rhMG53 does not seem to affect glucose metabolism (16, 129–133). Indeed, the lack of IRS-1 does not immediately give rise to diabetes because strong compensatory mechanisms exist between different IR subtypes (134, 135).

The aforementioned controversy may be attributed to the overlooked role of MG53 in pancreatic β-cells. In the absence of global insulin resistance, the IRs of pancreatic β-cells can inhibit high glucose-induced insulin secretion and their knockout can promote insulin secretion and improve glucose tolerance. However, this regulatory function of the IRs to β-cells does not occur in the presence of global insulin resistance (136). High glucose and insulin levels can promote the secretion of MG53 in striated muscle, and MG53 can induce the ubiquitination-dependent degradation and inactivation of IRs (15, 121). Under the assumption that MG53 can affect the function of pancreatic β-cells through IRs, MG53 overexpression would have a complicated effect on glucose metabolism in healthy and insulin-resistant humans ( Figure 2 ). A cohort study involving 283 subjects supports our hypothesis. This study found that although serum MG53 levels appeared to be unrelated to insulin resistance, subjects with impaired glucose metabolism had remarkably higher circulating levels of MG53 than healthy subjects. Furthermore, circulating levels of MG53 were found to be an independent risk factor for the development of type 2 diabetes rather than a simple disease marker, and elevated circulating levels of MG53 represent the diminished function of β-cells (137).

The above evidence suggests that MG53 has important implications for glucose metabolic disorders although the relationship between MG53 and insulin resistance is controversial. However, current research remains insufficient to elucidate its underlying mechanisms. Additional robust evidence is needed to explain the mechanism underlying the involvement of MG53 in glucose metabolism and validate the safety of rhMG53 in patients with metabolic disorders and cancer.

The potential adverse effects of MG53 on cancer cachexia must also be considered when applying rhMG53 in cancer therapy. Cancer cachexia, a common syndrome among patients with cancer, is characterized primarily by the loss of muscle tissue and inadequately relieved by nutritional means (138, 139). Changes in factors related to protein metabolism during cancer progression or treatment led to an imbalance between protein synthesis and degradation, resulting in muscle tissue reduction (140, 141). Reduced muscle mass in cancer cachexia is partly attributed to suppression of the anabolic signaling pathway induced by insulin-like growth factor1 (140). Cardiac atrophy and fibrosis in cancer cachexia are associated with the activated transforming growth factor-β (TGF-β)-mediated SMAD2/3 catabolic signaling pathway (142–145). MG53 inhibits the IGF-induced IRS-1/PI (3)K/Akt pathway, which is the best-characterized mechanism in cardiac and skeletal muscle myogenesis, through the ubiquitin-dependent degradation of IRS-1 (125, 139, 146, 147). Caveolin-1 plays an antifibrotic role in multiple organs and reduces cardiac fibrosis by repressing the TGF-β/Smad2 pathway (148, 149). MG53 can inhibit the expression of caveolin-1, thereby promoting TGF-β1/SMAD2-induced myocardial fibrosis (150). The activation of signal transducers and activator of transcription 3 (STAT3) has been implicated in promoting the progression of many cancers as well as exacerbating the loss of skeletal muscle tissue in cancer cachexia (151, 152). MG53 overexpression promotes the phosphorylation of STAT3, which thereby induces cardiac fibrosis, and its effect on cardiac lesions in cancer cachexia remains to be investigated (153).

Current research strongly suggests that MG53 is an important cancer therapy target, despite its potentially negative effects. Future researches should be focused on elucidating the mechanism of MG53’s role in cancer, glucose metabolism, and myogenesis, and on this basis, attempts should be made to retain the cancer therapeutic ability of MG53 while removing its side effects. MG53 mutants that retain membrane repair function without impairing glucose metabolism have been developed by eliminating the E3 ubiquitin ligase property of MG53 (128). In cancer therapy, however, the E3 ubiquitin ligase function of MG53 seems to play a crucial role. For the ubiquitination-dependent degradation of different proteins, MG53 may need to be activated at different sites, which could be the key to solving this problem (123, 128).

In summary, discussing the possible negative effects of MG53 on cancer treatment, especially in the context of varying degrees of insulin resistance and across gender, is urgently needed. If adverse effects are evident, developing safe mutants of MG53 may be a win-win approach.