Focusing on the molecular genetics and signaling pathways that play a critical role in cancer cells proliferation is helpful for more investigating the cancer pathogenesis and early diagnosis of HNSCC. Therefore, identifying the DEGs for HNSCC based on transcriptome data from TCGA RNA-seq may be useful in early diagnosis and detecting suitable drugs treatment. In the present study, TCGA data was used to evaluate the expression level of key genes and to assess the association between the expression level of selected genes with prognosis in HNSCC. The PPI network was constructed through the genes which showed a poor prognosis in this cancer. Our aim in the present study was to identify the hub prognostic genes that could be effective in the survival of patients and evaluate the relationship between candidate genes and immune cell infiltration, diagnostic marker, drug resistance, and sensitivity in HNSCC.
In our study, four of the 10 selected hub genes including TPX2, NUF2, BUB1, and DLGAP5 were considered to be the most likely independent prognostic biomarkers, prognostic factors, and key genes associated with HNSCC.
TPX2 is a microtubule-associated protein strictly regulated by the cell cycle which appears in the G1-S phase of the cell cycle and disappears after the completement of mitosis 20. In the phase of mitosis, TPX2 is released through Ras-related nuclear protein GTPase pathway and activated by phosphorylation of Aurora A. TPX2 has also been identified as a mitotic regulator of the Aurora A kinase 21,22. Recently results presented that Aurora-A and TPX2 co-expression in tumors23,24. overexpression of both Aurora-A and TPX2 was also recognized in samples from carcinoma compared to adenoma ovarian cancer patients in a combination of genome-wide expression data, in silico interaction network analysis, and real-time PCR mRNA measurements25–28.
In many tumor tissues, the high expression of TPX2 has been validated, such as colon cancer, esophagus cancer, bladder cancer, and liver cancer 29,30. TPX2 is also confirmed to be a molecular marker for an unfavorable prognosis in patients. Liu et al. showed that downregulated TPX2 could inhibit the expressions of MMP2 and MMP9 by inhibiting the activation of Akt so as to inhibit the invasion of liver cancer cells 31,32. It has been indicated that the high TPX2 level was associated with tumor progression and poor survival rate of gastric cancer33,34. Our results indicated that high expression levels of TPX2 predicted poor patient prognosis in HNSCC. In addition, our results revealed that TPX2 has a high diagnostic value for dividing the cancer samples and normal samples. Our results reveled that the high expression level of TPX2 could be reduced by some drugs like Ribavirin. In doing so, high expression of TPX2 in HNSCC could be associated with shorter-term survival and it could play critical role in cancer progression and drug resistance.
Mitotic kinases and mitotic checkpoint proteins play critical roles in cell division and maintenance of chromosome stability and dysregulation of these kinds of proteins could cause tumorigenesis 35,36. Budding uninhibited by benzimidazoles 1 (BUB1) is a mitotic checkpoint serine/threonine kinase that has been presented as an oncogene or tumor suppressor gene in many types of cancer, including breast cancer, pancreatic ductal adenocarcinoma, prostate, and gastric cancers. many studies have reported the aberrant expression of BUB1 correlates with a poor clinical prognosis in some cancers like breast cancer 37–40. Our outcomes showed that the expression level of BUB1 was up-regulated in HNSCC. Furthermore, the expression level of this gene is related to the low-survival rate of HNSCC patients and moreover, multivariate results confirm that BUB1 could be an independent prognosis factor in this type of cancer. Our finding revealed that the expression level of BUB1 could be used as a biomarker in HNSCC. The level of BUB1 could be reduced by some drugs like Glucosamine. Glucosamine is a naturally occurring monosaccharide with anti-inflammatory and antitumor effects 41. A previously studies results indicated that glucosamine inhibited G1/S cell cycle progression through affecting cyclin E degradation 21,42. In doing so, this drug could lower the expression level of BUB1 in HNSCC and could decrease the proliferation of cancer cells.
Nuf2, also known as CDCA1, is a key element of the Ndc80/Nuf2 complex that is required for the formation of stable kinetochore-microtubule attachments and chromosome alignment during mitosis. Nuf2 participates in the regulation of cell apoptosis and proliferation by regulating the binding of centromere and spindle microtubules to achieve the correct separation of chromosomes 43–45. Nuf2 promotes tumorigenesis and tumor development and is highly expressed in many human cancers, including serous adenocarcinoma, renal cell carcinoma, cholangiocarcinoma, colorectal, lung, ovarian, gastric, and bladder cancers 46,47. The High level of Nuf2 has been reported to associate with poor prognosis in non-small cell carcinoma patients and colorectal cancers 48,49. Furthermore, our results indicated that the expression level of NUF2 was up-regulated in HNSCC and its expression had a correlation with prognosis in this type of cancer. Moreover, some recent studies reported that down-regulation of Nuf2 expression could inhibit the proliferation of tumor cells, while overexpression of Nuf2 was associated with poor prognosis 50. A previous study showed that Nuf2 could also function as a potential biomarker in human tumor diagnosis and immunotherapy 51. our results also confirm that NUF2 could be utilized as a biomarker in HNSCC. Paying attention to the influence of the immune system in tumorigenesis enables us to improve cancer treatment and Immunotherapy. in this study, we evaluate the correlation between the expression level of NUF2 and immune cells like T cell CD8+. Identifying the drugs that could affect the level of cancer cells could be the beginning of suppressing the cancer progression. Our finding revealed that vemurafenib probably could lower the level of NUF2 in HNSCC.
The human discs large-associated protein 5 (DLGAP5) gene, which is mapped to chromosome 14q22.3, is a cell cycle regulator involved in carcinogenesis 52. DLGAP5 stabilizes k-fibers and promotes chromosome aggregation by regulating Kif18A localization and dynamics at the plus end of kinetochore microtubules (K-MTs) 53. Wang et al reported that DLGAP5 was upregulated in non-small cell lung cancer (NSCLC) and was correlated with a shorter survival time 23. Previous studies have also shown that the expression levels of DLGAP5 were upregulated in the bladder, prostate, and liver cancer, as well as leukemia, which was associated with poor prognosis52,54. Our results indicated that the high expression level of DLGAP5 was related to poor prognosis in HNSCC. Branchi et al reported that DLGAP5 was related to the nodal status, and the high DLGAP5 levels were correlated with a less favorable overall survival rate in distinct molecular colorectal cancer subtypes 52. Our finding indicated that DLGAP5 could be potent to be used as a diagnostic marker with high value. Our results demonstrated that the high expression level of DLGAP5 could be reduced by Ribavirin, Torcetrapib, and Glucosamine in some cancer that these outcomes suggest that these drugs probably could have an influence on the expression level of DLGAP5 in HNSCC.