Targeting NEK2 impairs oncogenesis and radioresistance via inhibiting the Wnt1/β-catenin signaling pathway in cervical cancer

Abstract

Background NEK2, a serine/threonine kinase involved in mitosis, has been found to function in chromosome instability, tumor progression and metastasis, but its role in cervical cancer radioresistance remains unknown. Methods We detected the protein levels of NEK2 in cervical carcinoma tissues and paired paracarcinoma tissues by immunohistochemistry. The roles of NEK2 in oncogenesis were examined using cell growth and colony formation assays, EdU assay, apoptosis assay as well as in vivo mouse model. γ-H2AX and Rad51 foci formation, neutral comet assay and clonogenic cell survival assay were applied to determine the radiosensitivity of cervical cancer cells. RNA-seq was performed to identify the downstream effector of NEK2. The gene expression levels were measured by Real-time PCR. Results We report that NEK2 protein level is overexpressed and correlated with the tumor stage and lymph node metastasis in cervical cancer tissues. Furthermore, we provided evidence that depletion of NEK2 impairs oncogenesis and enhances radiosensitivity in cervical cancer. Using RNA sequencing, we identify Wnt1 as a key downstream effector of NEK2. Knockdown of NEK2 downregulates the mRNA and protein levels of Wnt1, thereby inhibiting the activation of the Wnt/β-catenin signaling pathway. More importantly, the observed consequences induced by NEK2 depletion in cervical cancer cells can be partially rescued by Wnt1 overexpression. Conclusions Our results demonstrate that NEK2 activates the Wnt/β-catenin signaling pathway via Wnt1 to drive oncogenesis and radioresistance in cervical cancer, indicating that NEK2 may be a promising target for the radiosensitization of cervical cancer.

Prognostic evaluation and immune infiltration analysis of five bioinformatic selected genes in hepatocellular carcinoma

“…In contrast, SOCS2 and DNASE1L3 were negatively related factors, which were associated with cell cycle regulation. Previous studies have pointed out that cell cycle alterations and mitosis signalling pathways are closely associated with cancer progression and affect cancer immune infiltration 47–49 . Recent studies have also suggested that complement cascade may be linked with tumour‐promoting inflammation and cancer immune infiltration 50 …”

“…Previous studies have pointed out that cell cycle alterations and mitosis signalling pathways are closely associated with cancer progression and affect cancer immune infiltration. 47 , 48 , 49 Recent studies have also suggested that complement cascade may be linked with tumour‐promoting inflammation and cancer immune infiltration. 50 Thus, the target genes may contribute to the tumorigenesis and progression of HCC through promoting tumour cell proliferation and immune infiltration.…”

On Broken Ne(c)ks and Broken DNA: The Role of Human NEKs in the DNA Damage Response

“…The role of NEK2 in radioresistance was evaluated in HeLa, where NEK2 depleted cells show a significant increase in the tail comet and yH2AX foci formation, indicating that the NEK2 knockdown accelerates DNA damage [124].…”

“…Finally, the knockdown of NEK2 leads to negative regulation of WNT4/1, both on the mRNA and protein levels. This in turn leads to a down-regulation of beta-catenin and, consequently, to greater radioresistance and oncogenesis progression [124] (Figure 1).…”

A Unified Transcriptional, Pharmacogenomic, and Gene Dependency Approach to Decipher the Biology, Diagnostic Markers, and Therapeutic Targets Associated with Prostate Cancer Metastasis

“…The proteins mentioned above are also recognized as possible molecular targets in cancer. Indeed, knockdown or inhibition of PLK1 [77], CDK1 [78], AURKA [79], MELK [80,81], and NEK2 [82] resulted in reduction or repression of metastatic potential and invasiveness of various cancer types, including mCRPC and cervical cancer. The most prominent target in the list (Table 3) (as far as PrCa is concerned) is AR (androgen receptor).…”