MMS22L Expression as a Predictive Biomarker for the Efficacy of Neoadjuvant Chemoradiotherapy in Oesophageal Squamous Cell Carcinoma

Abstract

Long-term survival in oesophageal squamous cell carcinoma (ESCC) is related with pathological response after neoadjuvant chemoradiotherapy (NCRT) followed by surgery. However, effective biomarkers to predict the pathologic response are still lacking. Therefore, a systematic analysis focusing on genes associated with the efficacy of chemoradiotherapy in ESCC will provide valuable insights into the regulation of molecular processes. By screening publications deposited in PubMed, we collected genes associated with the efficacy of chemoradiotherapy. A specific subnetwork was constructed using the Steiner minimum tree algorithm. Survival analysis in Kaplan-Meier Plotter online resources was performed to explore the relationship between gene mRNA expression and the prognosis of patients with ESCC. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemical staining (IHC) were used to evaluate the expression of key genes in cell lines and human samples. The areas under the receiver operating characteristic (ROC) curves (AUCs) were used to describe performance and accuracy. Transwell assays assessed cell migration, and cell viability was detected using the Cytotoxicity Assay. Finally, we identified 101 genes associated with efficacy of chemoradiotherapy. Additionally, specific molecular networks included some potential related genes, such as CUL3, MUC13, MMS22L, MME, UBC, VAPA, CYP1B1, and UGDH. The MMS22L mRNA expression level showed the most significant association with the ESCC patient outcome (p < 0.01). Furthermore, MMS22L was downregulated at both the mRNA (p < 0.001) and protein levels in tumour tissues compared with that in normal tissues. Lymph node metastasis was significantly associated with low MMS22L expression (p < 0.01). MMS22L levels were inversely correlated with the NCRT response in ESCC (p < 0.01). The resulting area under the ROC curve was 0.847 (95% CI: 0.7232 to 0.9703; p < 0.01). In conclusion, low expression of MMS22L is associated with poor response to NCRT, worse survival, lymph node metastasis, and enhanced migration of tumour cells in ESCC.

Integrative pan-cancer landscape of MMS22L and its potential role in hepatocellular carcinoma

“…Nevertheless, not all reports suggested that MMS22L functioned as a cancer-promoting factor, promoting the occurrence and development of cancer. Recent studies have shown that low expression of MMS22L is associated with poor survival and lymph node metastasis and enhances tumor cell migration in ESCC ( Luo et al, 2021 ), suggesting the feasibility of MMS22L as a tumor suppressor gene. However, the function of MMS22L in the majority of human tumors is yet to be thoroughly investigated.…”

“…MMS22L, for instance, was detected in lung cancers as an oncogene involved in tumor proliferation and metastasis ( Nguyen et al, 2012 ). Conversely, a lower expression of MMS22L was associated with worse clinical outcomes in esophageal squamous cell carcinoma, suggesting MMS22L is a tumor suppressor ( Luo et al, 2021 ). Concurrently, many reports described that MMS22L affected the prognosis of patients by regulating drug sensitivity during treatment ( Liu et al, 2021 ).…”

UDP-glucose dehydrogenase (UGDH) in clinical oncology and cancer biology

“…In contrast, higher levels of UGDH are not ubiquitously associated with worse prognoses in all human cancer patient samples; for example, within esophageal cancer, there are conflicting findings. Liu et al, 2020 explored the prognostic value of lncRNA and found that UGDH-AS1 had lower expression levels in esophageal cancer samples while Luo et al, 2021 did not find a correlation between mRNA levels of UGDH and prognosis/survival for patients with esophageal cancer [ 12 , 13 ]. For prostate cancer, higher levels of UGDH have been observed in cancerous prostate acini than non-cancerous prostate tissue—a finding that established UGDH as a potential biomarker for PC [ 8 ].…”