The Oncogenic Roles of PTTG1 and PTTG2 Genes and Pseudogene PTTG3P in Head and Neck Squamous Cell Carcinomas

Abstract

Background: Head and neck squamous cell carcinomas are a group of heterogeneous diseases that occur in the mouth, pharynx and larynx and are characterized by poor prognosis. A low overall survival rate leads to a need to develop biomarkers for early head and neck squamous cell carcinomas detection, accurate prognosis and appropriate selection of therapy. Therefore, in this paper, we investigate the biological role of the PTTG3P pseudogene and associated genes PTTG1 and PTTG2 and their potential use as biomarkers. Methods: Based on TCGA data and the UALCAN database, PTTG3P, PTTG1 and PTTG2 expression profiles and clinicopathological features with TP53 gene status as well as expression levels of correlated genes were analyzed in patients’ tissue samples. The selected genes were classified according to their biological function using the PANTHER tool. Gene Set Enrichment Analysis software was used for functional enrichment analysis. All statistical analyses were performed using GraphPad Prism 5. Results: In head and neck squamous cell carcinomas, significant up-regulation of the PTTG3P pseudogene, PTTG1 and PTTG2 genes’ expression between normal and cancer samples were observed. Moreover, the expression of PTTG3P, PTTG1 and PTTG2 depends on the type of mutation in TP53 gene, and they correlate with genes from p53 pathway. PTTG3P expression was significantly correlated with PTTG1 as well as PTTG2, as was PTTG1 expression with PTTG2. Significant differences between expression levels of PTTG3P, PTTG1 and PTTG2 in head and neck squamous cell carcinomas patients were also observed in clinicopathological contexts. The contexts taken into consideration included: T-stage for PTTG3P; grade for PTTG3, PTTG1 and PTTG2; perineural invasion and lymph node neck dissection for PTTG1 and HPV p16 status for PTTG3P, PTTG1 and PTTG2. A significantly longer disease-free survival for patients with low expressions of PTTG3P and PTTG2, as compared to high expression groups, was also observed. Gene Set Enrichment Analysis indicated that the PTTG3 high-expressing group of patients have the most deregulated genes connected with DNA repair, oxidative phosphorylation and peroxisome pathways. For PTTG1, altered genes are from DNA repair groups, Myc targets, E2F targets and oxidative phosphorylation pathways, while for PTTG2, changes in E2F targets, G2M checkpoints and oxidative phosphorylation pathways are indicated. Conclusions: PTTG3P and PTTG2 can be used as a prognostic biomarker in head and neck squamous cell carcinomas diagnostics. Moreover, patients with high expressions of PTTG3P, PTTG1 or PTTG2 have worse outcomes due to upregulation of oncogenic pathways and more aggressive phenotypes.

Pseudogene Transcripts in Head and Neck Cancer: Literature Review and In Silico Analysis

“…In HNC, some pseudogene transcripts have been studied and associated with tumor aggressiveness, HPV16 infection, and prognosis [24][25][26][27][28]. However, their role in HNC remains poorly explored, while patients' therapy resistance and poor survival rates highlight the need of finding novel molecular biomarkers.…”

“…Based on The Cancer Genome Atlas (TCGA) data and the University of Alabama Cancer Database (UALCAN), Grzechowiak et al [27] described that PTTG3P (pituitary tumor-transforming 3 pseudogene) pseudogene transcript abundance was correlated with HNC lower T-stage (T1 or T2), positive HPV16 status, and poor prognosis [27]. Gene Set Enrichment Analysis indicated that PTTG3P was correlated with genes involved in DNA repair, oxidative phosphorylation, and peroxisome pathways [27].…”

Overexpressing PTTG Family Genes Predict Poor Prognosis in KIRC

“…PTTG was originally separated from the tumor of the pituitary tumor, a multi-function protein, involved in cell cycle, cell proliferation, angiogenesis, and metastasis [4]. PTTG consistins of two genes with protein products PTTG1 and PTTG2, and a processed pseudogene PTTG3P, has been described in the context of carcinogenesis [5]. Overexpression of PTTG was reported in many cancers including lung, gastric, kidney, pancreatic, breast cholangiocarcinoma, psoriasis, Adrenocortical Carcinomacarcinoma, hepatocellular carcinoma, glioblastoma, esophageal squamous cell carcinoma, and prostate cancer [6][7][8][9][10][11][12][13][14][15].…”

The target E2F family gene PTTG1 for prediction of distant relapse-free survival in breast cancer patients receiving taxane and anthracycline-based NACT

“…PTTG1, described in the context of carcinogenesis [13][14][15][16], as a target gene of E2F family [17,18] has been implicated in multiple cellular processes including, but not limited to, cellular differentiation, apoptosis, DNA damage repair, maintains chromosomal stability and angiogenesis in breast cancer [19][20][21]. Quiet a lot of breast cancer patients couldn't bene ted from NACT and show distinct responses to NACT even when their clinicopathological characteristics are same or similar because of the molecular differences, and the absence of well-de ned molecular target [22,23].…”