HIPK2 Overexpression and Its Prognostic Role in Human Papillomavirus-Positive Tonsillar Squamous Cell Carcinoma

Abstract

Tonsillar squamous cell carcinomas (TSCCs) are the most common human papillomavirus- (HPV-) associated oropharyngeal cancers with poor prognosis. Homeodomain-interacting protein kinase 2 (HIPK2) is a central regulator of p53, which participates in apoptosis during the DNA damage response. HIPK2 is involved in HPV-associated uterine cervical and cutaneous carcinogenesis through its binding of HPV E6, thereby preventing apoptosis and contributing to tumor progression. However, its clinical and prognostic significance in TSCC remains unclear. HIPK2 mRNA levels were analyzed in 20 normal tonsils and 20 TSCC specimens using real-time reverse transcription polymerase chain reaction. Immunohistochemistry of HIPK2 was performed in 79 resected specimens. HIPK2 was expressed in 57% of the TSCCs, and HIPK2 protein expression and HIPK2 mRNA levels were higher in TSCCs than in normal tonsils. HIPK2 overexpression was associated with poorly differentiated carcinoma and low alcohol consumption and was an independent prognostic factor for overall survival and disease-free survival (DFS) in TSCC and a negative independent prognostic factor for DFS in patients receiving postoperative radiotherapy. HIPK2 overexpression had a significant association with poorer DFS in HPV-positive TSCCs, but not in HPV-negative tumors. HIPK2 overexpression may be a potential prognostic marker for predicting prognoses and a high risk of recurrence, particularly in patients with HPV-positive TSCC.

HIPK2 reduces the resistance of gastric cancer cells to cisplatin via p53 pathway

“…HIPK2 affects the progression of multiple cancer types. HIPK2 overexpression was reported in papillomavirus-positive tonsillar squamous cell carcinoma and correlated with the prognosis of patients [22]. HIPK2 regulates malignant growth through the phosphorylation of Notch1 [23].…”

Differences in gene expression despite identical histomorphology in sinonasal intestinal‐type adenocarcinoma and metastases from colorectal adenocarcinoma

“…In colorectal cancers, an increase in expression of HIPK2 compared with normal colon cells is found (with an inverse correlation between HIPK2 expression and tumor staging) [58]. In addition, the loss of HIPK2 has been linked with aggressive behavior and tumor progression in CRC and thyroid cancers [57]. As HIPK2 regulates the final step of the cell cycle via phosphorylation of histone H2B at the midbody, the lack of HIPK2 leads to cytokinesis failure and chromosomal instability often seen in CRC [56,59].…”

An Alternative Splice Variant of HIPK2 with Intron Retention Contributes to Cytokinesis

“…In contrast to these observations, HIPK2 has been shown to have prosurvival and proproliferative oncogenic activities in different types of cancers, including a Drosophila leukemia model [32,33]. Increased HIPK2 expression with or without gene amplification has been observed in pilocytic astrocytoma [34,35], cervical [36], and renal carcinomas [37], while HIPK2-mediated protection against genotoxic insults has been found in NRF2-overexpressing tumor cells [38]. Strong proproliferative activity of HIPK2 has also been related to kidney and skin fibrosis, in which excessive fibroblast proliferation is coupled with the deposition of extracellular matrix and epithelial-to-mesenchymal transition [39,40].…”