In this study, we elucidated the clinical significance of PYK2 in early-stage cervical cancer patients for the first time. The high expression level of PYK2 was significantly associated with unfavorable outcomes. We built nomogram models for OS and DFS depend on three prognostic factors, which includes PYK2 expression. Furthermore, by using loss-of-function approaches, we found that PYK2 downregulation hampered the cellular capabilities of proliferation, migration and invasion in an obvious manner.
Our study showed that differentiation grade was positively correlated with PYK2 expression, indicating a probability that tumor with higher expression of PYK2 was associated with a greater progressive and invasive risk. PYK2 is found to involved in the biological processes of tumorigenesis, tumor development and invasion via several processes[25, 26]. In hepatocellular carcinoma, PYK2 can promote cancer progession by activiting PI3K/AKT signaling pathways[19]. It was reported that PYK2 can stabilize TAZ protein and negatively regulate the Hippo pathway to promote cell growth and prevent apoptotic cell death in triple-negative breast cancer[16]. Additionally, overexpressed Pyk2 is uncovered to modulate Wnt/b-catenin pathway by phosphorylating GSK3bY216, which initiates and reinforces intestinal tumorigenesis[27]. PYK2 was also found to take part in metastasis or recurrence in different tumors. As reported in breast cancer, a signalling network between EGFR, c-Met, PYK2 and STAT3 can potentiate EMT and contribute to cancer metastasis[7]. Moreover, miR-23b may regulate migration by targeting PYK2 via regulation of EMT in hepatocellular carcinoma[28]. Nevertheless, no significant correlation was found between PYK2 expression and lymph node metastasis in this study with a possibility that the samples included were all relatively early-stage patients with a small probability of lymph node metastasis.
As a novel and high-value therapy for cancer, molecule inhibitors of PYK2 obtain continuous attention recent years. PF-00562271 is a widely-concerned PYK2 inhibitor and has been reported to produce robust anti-tumor effects indifferent cancer cells and xenograft tumor models, such as pancreatic cancer, prostate cancer, bone tumors and hepatocellular carcinoma[29–32]. As a second-generation inhibitor of PYK2, VS-6063 was rationally designed to have less potential for drug-drug interaction than PF-00562271[33]. Both PF-00562271 and VS-6063 were well-tolerated in patients in Phase 1 studies and need further investigation as promising therapeutic drugs[34, 35]. We revealed the tumor-promoting role of PYK2 in cervical cancer and further exploration of PYK2 inhibitors are needed to confirm the effect of it on cervical cancer cells. Furthermore,we constructed a prognostic nomogram model to predict the survival rates by integrating PYK2 expression and other clinicopathological prognostic factors. The Harrell’s concordance index indicated a good prognostic ability of the model, which makes it available for clinical use.
However, our study had several limitations. Firstly, the clinical data analysis were conducted on a limited cohort size. Secondly, the patients involved were all in the early-stage of cervical cancer with relatively favorable prognosis. Therefore, a larger cohort of patients with high-risk pathological factors are needed in the subsequent study. Thirdly, the underlying molecular mechanisms and signalling pathways of PYK2 involved in the development and progression of cervical cancer remain unknown, which needs further exploration.