Expression of the NEK family in normal and cancer tissue: an immunohistochemical study

Abstract

Background: The NEK serine/threonine protein kinases are involved in cell cycle checkpoints, DNA damage repair, and apoptosis. Alterations in these pathways are frequently associated with cell malignant cellular transformations. Thyroid cancer is the most common malignant tumour in the endocrine system. Despite good treatment methods, the number of cases has increased significantly in recent years. Here, we studied the expression of NEK1, NEK2, NEK3, and NEK5 in different types of normal and malignant tissues, using tissue microarray analysis, and identified NEKs as potential markers in thyroid malignancy. Methods: The studied cases comprised multiple cancer tissue microarrays, including breast, colon, esophagus, kidney, lung, pancreas, prostate, stomach, thyroid and uterine cervix, as well as 281 patients who underwent thyroid resection for thyroid cancer or thyroid nodules. The expression of NEK1, NEK2, NEK3, and NEK5 was analyzed by immunohistochemistry. The expression pattern was evaluated in terms of intensity by two methods, semiquantitative and quantitative, and was compared between normal and cancer tissue. Results: We analysed the expression of each member of the NEK family in a tissue-dependent manner. Compared to normal tissue, most of the evaluated proteins showed lower expression in lung tumour. However, in the thyroid, the expression was higher in malignant tissue, especially for NEK 1, NEK3 and NEK5. Concerning characteristics of the thyroid tumour, such as aggressiveness, NEK1 expression was higher in tumours with multifocality and in patients with lymph node metastasis. NEK3 expression was stronger in patients with stage II, that involved metastasis. NEK5, on the other hand, showed high expression in patients with invasion and metastasis and in patients with tumour size > 4 cm. Furthermore, this work, demonstrated for the first time a high specificity and sensitivity of over-expression of NEK1 in classical and follicular variants of papillary thyroid cancer and NEK3 in tall-cell papillary thyroid cancer. Conclusion: Taken together, the NEK protein kinases emerge as important proteins in thyroid cancer development and may help to identify malignancy and aggressiveness features during diagnosis. Trial registration: This study was retrospectively registered. www.accamargo.org.br/cientistas-pesquisadores/comitede-etica-em-pequisa-cep.

Checking NEKs: Overcoming a Bottleneck in Human Diseases

“…In a recently published paper by our group, a direct link between NEK1 and thyroid cancer was observed [67]. Tissue microarray analysis revealed increased expression of NEK1 in classical and follicular variants of papillary thyroid cancer, allowing us to use these levels of expression to discriminate the malignancies with high specificity and sensitivity.…”

“…Additionally, NEK3 overexpression is related to poor overall survival [129]. Similarly, an analysis of papillary thyroid carcinomas and follicular thyroid carcinomas revealed that the expression of NEK3 is stronger in tall-cell papillary thyroid cancer, with the highest levels being observed in patients with metastases [67].…”

“…An analysis of thyroid tissues revealed a high expression of NEK5 in the tissues of patients with invasion and metastasis. Additionally, the expression of NEK5 was related to the patient's tumor size, showing higher expression with an increase in the tumor size [67].…”

Fractionation-Dependent Radiosensitization by Molecular Targeting of Nek1

“…Up-regulation of Nek1 in glioma tissue correlated with the clinical grade and Karnofsky performance scale, and was significantly associated with a poor OS, while an siRNA-mediated KD of Nek1 sensitized glioblastoma cells to the drug temozolomide [23]. Nek1 expression was elevated in thyroid tumors with multifocality and in patients with lymph node metastasis [44]. Nek1 is further reported to be associated with a decreased sensitivity to DNA damaging agents in renal cell carcinomas [45] and to be part of a 12-gene tumor signature to predict progression of non-invasive to muscle-invasive bladder cancer [24].…”

“…Our results about the association of Nek1 with the clinical outcome, its impact on clonogenic survival and tumor growth in vivo indicate the protein to represent a valuable target for radiation sensitization. In addition, given an overexpression of multiple members of the Nek family in human malignancies and overlapping functional properties [16,44], the entire family should be considered for use in pharmacological approaches to increase radiation or chemotherapy response in anti-cancer treatment.…”