Myelin and Lymphocyte Protein (MAL): A Novel Biomarker for Uterine Corpus Endometrial Carcinoma

Abstract

Purpose Myelin and lymphocyte protein (MAL) plays an essential role in esophageal cancer, classic Hodgkin’s lymphoma and breast cancer. However, its role in uterine corpus endometrial carcinoma (UCEC) has not been explored. Therefore, the current study sought to explore the role of MAL in UCEC. Patients and Methods Differentially expressed genes (DEGs) were identified by using Limma package in R based on TCGA-UCEC data. Kaplan–Meier plotter analysis was performed to explore the prognostic value of MAL. Function enrichment analyses were performed using GSVA. Further, roles of MAL in UCEC were validated using clinical cohort, which included 120 tumor and adjacent tissues. qRT-PCR and immunohistochemistry analyze the samples. Chi-square tests were performed to explore the associations between MAL expressions and clinicopathological features. Results The findings showed that overexpression level of MAL in tumor was correlated with worse survival (p = 0.000424). MAL exhibited predictive power for survival time of UCEC patients (3 years: AUC = 0.635; 5 years: AUC = 0.635). Notably, high expression level of MAL was correlated with advanced stage of UCEC. MAL overexpression was significant in UCEC with microsatellite instability (MSI). Enrichment analysis showed that MAL was enriched mainly in MYC targets, epithelial mesenchymal transition and KRAS signaling. Furthermore, MAL was associated with infiltration of immune cells in the tumor micro-environment and immune checkpoint. Analysis showed a positive association between MAL and T cell (CD4+ memory resting). Correlation analysis showed that MAL was significantly positively correlated with several immune checkpoint, including CD274 (R = 0.3389, p = 0.0081), LAG3 (R = 0.2913, p = 0.0229), PDCD1LG2 (R = 0.5345, p < 0.0001). The prognosis value of MAL was confirmed through the experiment. Conclusion The findings of the current study indicated that MAL is an effective prognostic biomarker and potential therapeutic target for UCEC patients. These results indicated that MAL functions as a diagnosis and therapeutic marker in UCEC treatment.

The MAL Family of Proteins: Normal Function, Expression in Cancer, and Potential Use as Cancer Biomarkers

“…However, in the case of STAD, one study showed that MAL hypermethylation, which was accompanied by MAL mRNA downmodulation [75], has a favorable prognosis, while MAL mRNA downmodulation correlated with an unfavorable prognosis in another study [76]. Consistent with the analysis illustrated in Figure 7, the use of IHC confirmed that a high level of MAL expression is associated with unfavorable outcome in UCEC [152]. With regard to the other MAL-family members, IHC analysis confirmed that high levels of MAL2 [99] and MYADM [117] are associated with poor outcome in PAAD and STAD, respectively.…”

“…Thus, exogenously-expressed MAL in breast [67], esophageal [129], cervical [87], colorectal [113], lung [84], and head and neck [71] cancer cell lines reduced cell migration and invasion, or increased apoptosis, and reduced tumor size in nude mice [71,84,129]. Similar effects were observed for exogenous MAL2 in prostate [152], pancreatic [99], lung [149], and liver [108] cancer cells; for exogenous MALL in colorectal cancer cells [113]; and for CMTM8 in liver [153], pancreatic [119], and urothelial [116] cancer cells. These observations suggest that at least some of the MAL-family genes downmodulated in tumors might have a tumor-suppressor function in specific organs and tissues.…”

CXC chemokines: Potential biomarker and immunotherapeutic target for uterine corpus endometrial carcinoma

“…Advances in detection mean that most patients with UCEC can be diagnosed or treated at an early stage, improving survival. However, a significant number of patients are diagnosed at advanced stage or harbor occult metastatic lesions, causing tumor recurrence because of the limited response to therapies [ 34 ]. In addition, conventional diagnostic approaches provide limited prognostic information that could aid clinical judgement and provide therapeutic guidance [ 35 ].…”

Research advances of MAL family members in tumorigenesis and tumor progression (Review)

“…The Mal family encompasses members that are widely distributed across various bodily systems, with their involvement in the digestive, respiratory, urinary and circulatory systems being successively uncovered. These proteins play crucial roles in tumorigenesis signaling pathways and cell cycle regulation, thereby influencing tumor development and patient prognosis (38,39,42,68,136,164). However, the current understanding of their specific molecular mechanisms remains limited.…”

“…Evidence supporting its tumor suppressor activity includes ectopic MAL expression inhibiting growth and reducing viability of cancer cells in nude mouse models, blocking G1/S transition and increasing Fas-mediated apoptosis (32,(62)(63)(64)(65)(66)(67). However, MAL acts as an oncogenic factor in endometrial carcinoma and certain lymphomas, such as thymic large B cell lymphomas but not in nodal diffuse large B cell lymphomas (39,(68)(69)(70)(71)(72).…”