Our study showed that MMRN1 was significantly down-regulated in 22 tumors and significantly up-regulated in 7 tumors. Immunohistochemistry analysis also demonstrated that MMRN1 was highly expressed in normal tissues of the liver, thyroid, and kidney and low in the corresponding tumor tissues. According to the available studies, MMRN1 expression was downregulated in thyroid cancer and non-small cell lung cancer[7, 23, 24], which is consistent with our analysis. Furthermore, MMRN1 was shown to be upregulated in epithelial ovarian cancer[8, 25], which contradicts our analysis. It is possible because we analyzed ovarian serous cystadenocarcinoma rather than total epithelial ovarian cancer and that the different features possessed by different subtypes led to this result. However, overall, MMRN1 is a gene that is down-regulated in expression in a variety of human cancers and is associated with tumor staging.
As a disease highly associated with genetics, tumors have received increasing attention to predict the prognosis of tumor patients by detecting gene expression. The ones that are well known and have been extensively studied are RAS, MYC, and p53[26–28]. However, finding biomarkers that can effectively predict tumor prognosis is still a challenge. Our analysis showed that MMRN1 expression was significantly correlated with OS, DSS, and PFI in a variety of tumors, suggesting the possibility of MMRN1 as a prognostic risk factor. Notably, high expression of MMRN1 in LAML was positively correlated with poor OS, which has been demonstrated. In pediatric acute myeloid leukemia, high MMRN1 expression was associated with poorer OS, EFS, and a higher risk of relapse, as reported by George S. Laszlo et al[10].
Because MMRN1 is a factor V binding protein, the high relevance of MMRN1 to the hemostatic coagulation pathway is inevitable. MMRN1 can synergistically enhance platelet adhesion[4], so it makes sense that enrichment analysis would appear to be associated with hemostatic coagulation as well as platelets. Other than that, it is worth exploring further the role of MMRN1 in more areas. It is worth noting that the pathways obtained from KEGG enrichment analysis include ECM-receptor interaction, Focal adhesion, Cytokine-cytokine receptor interaction, MicroRNAs in cancer, Human papillomavirus infection, and PI3K-Akt signaling pathway. All of these play a role in cancer. This suggests a wide scope for exploring the role played by MMRN1 in tumors and provides a direction for further study of the mechanism of MMRN1.
Tumor immunity is a very important factor affecting tumor progression. Tumorigenesis and progression are associated with dysfunction of the immune system. By interfering with the immune system of cancer patients, cancer immunotherapy is also showing signs of success[29]. However, further exploration of basic tumor immunology is very important for the successful clinical treatment of cancer patients with immunotherapy[30]. Interestingly, by analyzing the correlation between MMRN1 and immune inhibitors, immune stimulators, and MHC molecules, we found that MMRN1 was positively correlated with immune-related genes in most tumors and that MMRN1 was largely positively correlated with immune infiltration, implying that MMRN1 seems to play an important role in immune infiltration. From the aforementioned pathway enrichment analysis, we also found that MMRN1 was associated with pathways such as cytokine-cytokine receptor interactions. It is well known that in the tumor microenvironment, immune-related cells and various effector molecules in the microenvironment act on tumor cells under normal conditions to arrest tumor progression, while tumor cells evade the immune system in various ways, and the cytokine-cytokine receptor interaction pathway plays a crucial role[31, 32]. This suggests the possibility that MMRN1 acts on tumor immunity by influencing cytokine-cytokine receptor interactions, but this is only a conjecture and only provides a new direction for future MMRN1 research.
Genetic alterations and epigenetic alterations contribute to the development and progression of cancer. Cancer is often accompanied by abnormal DNA methylation[33]. As a key epigenetic process, DNA methylation acts as a switch that controls cellular transcription[34]. Changes in DNA methylation in cancer are considered promising targets for the development of powerful diagnostic, prognostic, and predictive biomarkers[35]. However, there is almost a gap in the research related to MMRN1 in tumors. We investigated MMRN1-associated genetic variation and MMRN1 methylation. Among various human cancers, the overall frequency of genetic changes in MMRN1 in cancer is relatively low, but MMRN1 methylation was shown to be closely associated with MMRN1 mRNA expression in most cancer types and showed a negative trend, especially in CHOL and LGG. We also analyzed the promoter methylation levels of MMRN1 in cancers and found that MMRN1 methylation levels were higher in BRCA and CHOL, but lower in LIHC and TGCT. This change in methylation level is likely to alter the expression and action of MMRN1 in tumors.
Alterations in the cancer genome may strongly influence the clinical response to treatment. Molecular biomarkers for identifying drug susceptibility can be found by analyzing the relationship between cancer gene alterations and drug susceptibility[36]. Our analysis found that MMRN1 correlated with the sensitivity of several drugs. For the GDSC database, MMRN1 mRNA was strongly negatively correlated with the sensitivity of GW-2580, TL-1-85, OSI-930, Sorafenib, and NG-25. For the CTRP database, MMRN1 mRNA was strongly and negatively correlated with the sensitivity of BRD-K30748066, sotrastaurin, and narciclasine. But more evidence is needed on whether MMRN1 can be used as a molecular biomarker to identify drug susceptibility.
In conclusion, our analysis demonstrated a significant relationship between MMRN1 and prognosis, tumor immunity, and drug sensitivity of several tumors. In particular, in tumor immunity, MMRN1 was positively correlated with multiple immune-related molecules and immune cell infiltration. However, the possibility of MMRN1 as a prognosis-related molecule and the role it plays in tumor immunity need to be further explored.