Protein is the material basis of life, the basic organic matter that constitutes cells, and the main undertaker of life activities. Membrane proteins play an important role in many life activities of organisms, such as cell proliferation and differentiation, energy conversion, signal transduction and material transport. It is estimated that about 60% of drug targets are membrane proteins. Abnormal membrane protein expression causes a variety of diseases including cancer. In recent years, research on the structure and function of membrane proteins has become a hot topic . However, the exact mechanism or the role of plasma membrane proteins in renal cell carcinoma still unclear. In this study, we downloaded a large number of ccRCC data from TCGA, which helped to obtain a comprehensive analysis of plasma membrane proteins in ccRCC patients. After compared gene expression between ccRCC and normal patients’ tissues, we identified 159 DEPMPs. GO and KEGG pathway enrichment analysis shows that these PMPs were mainly enriched in actin filament organization. Studies have found that actin filament organization plays a role in a variety of tumors such as prostate cancer, head and neck cancers and melanomas . However, there is no reports about actin filament organization in renal cancer, further experimental exploration is needed in the future.
101 survival related PMPs were screened out by univariate Cox regression analysis. With the help of online websites, we could learn more about the molecular characteristics and internal or external relationships of those survival related PMPs. First, the protein-protein network shows that those PMPs interact closely with each other. Then, the TF-PMP network shows that transcription factors FOXM1, NCAPG, CENPA, MYBL2, EOMES, IRF4, IKZF1 and BATF are closely related to these PMPs. Some previously studies have shown those TFs were connected with occurrence and progression of ccRCC [12–18]. Base on the above findings, we have good reason to believe that those PMPs play a significant role in ccRCC as a whole.
In order to explore whether these survival related PMPs have prognostic value in ccRCC, we constructed a prognostic model according to multivariate cox regression analysis. Survival and ROC analysis indicated that the prognostic model shows considerable value of prognostic prediction. The positive results were also confirmed by external data. What’s more, we did a comprehensive analysis of the relationship between the model and clinical parameters. The risk score was higher for advanced grade, stage, and distant metastasis patients. In addition, we also found these nine PMPs involved in this model were closely related to tumor grade, stage and distant metastasis respectively.
With the help of an online database, we explored these PMPs further. We found that mutations are common in these genes and CYFIP2 was the most frequently mutated gene. CYFIP2, cytoplasmic FMR1-interacting protein 2, was reported to be a candidate p53 target gene. CYFIP2-induced apoptosis is part of a coordinated p53-dependent response in cancer cells . Nevertheless, studies on CYFIP2 in kidney cancer are rare. The survival analysis of CYFIP2 in different subgroups include tumor grade, race, and gender show that CYFIP2 was closely related to the overall survival of ccRCC patients. Due to the high frequency of CYFIP2 mutation, we think it is necessary to pay more attention to its certain mechanism in ccRCC. Current research shows that the remaining eight PMPs are all closely related to cancer too. ULBP2 expression was reported to increase in ovarian cancer cells and high expression of ULBP2 is an indicator of poor prognosis in ovarian cancer . EPB41L4A is a target gene for the Wnt/β-catenin pathway. High expression of EPB41L4A indicates good survival in multiple myeloma . Gene fusions are frequent early genomic rearrangements in prostate cancer. The unique in-frame MPP5–FAM71D fusion product is important for proliferation of prostate cancer cells . CASP4, a member of the inflammatory caspases, has been shown to promote the proliferation of many kinds of cancer cells . Xie et al found a novel SNP of ARHGEF12 that may involve ARHGEF12-RhoA-p38 signaling in erythroid regeneration in ALL patients after chemotherapy . Recent advances have demonstrated that kinetochore‑associated proteins are upregulated and serve significant roles in the carcinogenesis of numerous types of cancer. KNTC1 may have an essential role in mediating cell viability and apoptosis in human ESCC cells and may serve as a novel therapeutic target for esophageal squamous cell carcinoma . Ubiquitin-conjugating enzyme E2S (UBE2S) knockdown suppressed the malignant characteristics of breast cancer cells, such as migration, invasion, and anchorage-independent growth . In this study, we found that they were associated with overall survival in patients with ccRCC. However, up to now, existing research cannot fully explain the certain mechanism of those genes. Thus, more large sample prospective studies and basic experiment further defined the relation between kidney cancer and plasma membrane protein is needed.
It should to be noted that some limitations exist in this study. First, at present, the molecular mechanisms behind key PMPs are still covered, our study need to be validated by more experiment. Second, other researches may draw different results due to different experimental variations and statistical methods. Beyond these limitations, this study focused on potential molecular mechanisms and clinical significance of PMP. we hope this prognostic model could inspire medical scientists on ccRCC prognosis and precise therapy.