p53R2 is oncogenic in human cervical cancer

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p53R2 overexpression in cervical cancer promotes AKT signaling and EMT, and is correlated with tumor progression, metastasis and poor prognosis

Cervical cancer is a public health problem, representing the fourth most commonly diagnosed cancer in women and the seventh overall, with an estimated 527,600 new cases in 2012 across the world.¹ There were an estimated 265,7000 deaths from cervical cancer worldwide in 2012, accounting for 7.5% of all female cancer deaths and this number is expected to increase up to 410,000 by 2030.² For those advanced cervical cancer patients not amenable to curative treatments, such as surgery and radiation, palliative chemotherapy remain the standard of care. Although systemic treatment has entered into the era of targeted drugs, the antitumor efficacies of current therapies are still limited. Bevacizumab, the anti-VEGF (vascular endothelial growth factor) monoclonal antibody, is the only targeted drug approved by the FDA for the treatment of patients with metastatic, recurrent, or persistent cervical cancer, could improve overall survival from 13.3 months to 17 months.³ In this context, there is a great need for identifying reliable biomarker and new therapeutic targets for cervical cancer.

Ribonucleotide reductase small subunit p53R2, also called RRM2B, is a p53-responsive factor involved in such functions as DNA replication and repair, cell cycle arrest, and mitochondrial homeostasis. With its critical role in deoxy ribonucleotide biosynthesis and DNA repair, dysregulation of p53R2 was suggested to be involved in tumor biology. Although expression level of p53R2 has been investigated in several human cancers, p53R2's roles in cancer progression and malignancy still remain controversial.⁴ For instance, p53R2 has metastasis-suppressing potential in human colorectal cancer and liver cancer, but is also considered as a progressive biomarker in esophageal squamous cell carcinoma and oral cancer. Viable hypotheses have been proposed to explain the dual role of p53R2.⁵ P53R2 inhibits cell proliferation and cell survival by inducing p21 and further cell cycle arrest. On the other hand, p53R2 repairs DNA and acts as scavenger of ROS, maintaining cell survival of both cancerous and non-cancerous cells, which causes cancer progression through exerting resistance to DNA damaging therapies such as clofarabine and radiotherapy.^6,7 Up to now, p53R2's biologic functions and the potential regulatory mechanisms in cervical cancer remain unknown.

Recently, Dr. X.F. Steven Zheng's group studied the function and mechanism of p53R2 in cervical cancer,⁸ and found that p53R2 expression is significantly upregulated at both mRNA and protein levels in cervical cancer tissues and cells, and the overexpression of p53R2 was associated with increased risk of pelvic lymph node metastasis and cancer relapse. They further demonstrated that p53R2 is an independent factor for predicting overall survival and disease-free survival of cervical cancer patients, implying p53R2 may be a potential progressive/prognostic biomarker for cervical cancer. Through further investigation, they discovered the unconventional oncogenic functions of p53R2 in cervical cancer–involvement in malignant growth regulation (Fig. 1). They revealed that p53R2 promotes cervical cancer through at least two distinct mechanisms. First, p53R2 stimulates PI3K/AKT signaling as evidenced by the dependence of AKT phosphorylation and repression of PTEN expression on p53R2. Second, p53R2 enhances epithelial-mesenchymal transition, which provides a mechanistic explanation for increased metastasis in high p53R2 expressing cervical cancer patients. All these intriguing findings suggest that p53R2 is a potential therapeutic target for cervical cancer, which shed new light on p53R2's non-DNA repair function. Given the evidence that depletion of p53R2 using small molecules or siRNAs with high specificity could sensitize cancer therapy, it is reasonable to propose that inhibition of p53R2 may improve the efficiency of cervical cancer treatment.

Figure 1. p53R2 is oncogenic in human cervical cancer. p53R2 promotes PI3K/AKT signaling and epithelial-mesenchymal transition, which contributes to cervical cancer growth and metastasis.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.