Abstract
p63 is a transcription factor p53 family. Two major isoforms of p63, TAp63 with transactivation (TA) domain and ΔNp63 with truncated TA domain, have been reported to play opposing roles either in tumor suppression or oncogenic function. Little is known about the association of these two isoforms of p63 in the carcinogenesis of cervical cancer. In this study, the mRNA expression levels of TAp63 and ΔNp63 in 40 normal, 30 low-grade squamous intraepithelial lesions (LSIL), 38 high-grade squamous intraepithelial lesions (HSIL), and 52 cervical cancer formalin-fixed paraffin-embedded tissues were examined using quantitative reverse transcription polymerase chain reaction (RT-qPCR). We analyzed the association between the ΔNp63 and ΔN/TAp63 mRNA expression ratio and clinicopathological parameters and compared disease-specific survival of each ΔNp63 mRNA expression and ΔN/TAp63 mRNA expression ratio. The ΔN/TAp63 mRNA expression ratio in cervical cancer showed higher sensitivity than the mRNA expression levels of ΔNp63 (52.0% vs 44.2%). The level of ΔN/TAp63 mRNA expression ratio in precancerous LSIL and HSIL was higher than in normal tissues (P = 0.01 and P = 0.003) and lower than in cervical cancer tissues (P = 0.03 and P = 0.02). Besides, the positive ΔN/TAp63 mRNA expression ratio was associated with bulky tumor size and high expression of Ki-67, the proliferation marker, in cervical cancer (P = 0.04 and P = 0.02). The cervical cancer patients with the positive ΔN/TAp63 mRNA expression ratio showed worse survival compared to those who with the negative expression ratio of ΔN/TAp63 (HR = 5.7, 95% CI: 1.6–19.9). In conclusion, the balance of TAp63 and ΔNp63 is closely related to the carcinogenesis of cervical cancer. The ΔN/TAp63 mRNA expression ratio could be useful as a diagnostic and prognostic marker of cervical cancer.
Highlights
Cervical cancer is one of the leading causes of mortality and is ranked as the third most common cancer in women worldwide [1]
Compared to the mRNA expression levels of TAp63, ΔNp63 mRNA expression levels were significantly higher in the ME-180, SiHa, CaSki, and C33A cell lines (P < 0.0001, P = 0.0003, P = 0.01, and P = 0.039, respectively) (Fig 1A)
ΔN/TAp63 mRNA expression ratio of cervical cancer and normal formalin-fixed paraffin-embedded (FFPE) tissues and Receiver operating characteristic (ROC) analysis. (A) The ΔN/TAp63 mRNA expression levels in 52 cervical cancer FFPE tissues and 40 normal FFPE tissues were measured by RT-qPCR. (B) ROC analysis showed that the AUC of the ΔN/ TAp63 mRNA expression ratio was 0.8149
Summary
Cervical cancer is one of the leading causes of mortality and is ranked as the third most common cancer in women worldwide [1]. According to the World Health Organization, cervical cancer accounts for approximately 530,000 new cases and 266,000 deaths per year worldwide [2]. The p53 family consists of a transactivation (TA) domain, a DNA-binding domain, and an oligomerization domain. These proteins induce cell cycle arrest and apoptosis [4,5,6]. P1 leads to the TAp63 isoform which contains a TA domain at the N-terminus, and P2 synthesizes the ΔNp63 isoform, which lacks the TA domain [5, 7]
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