Abstract
Dysregulations of the NEK2 and PIM1-3 kinase signaling axes have been implicated in the pathogenesis of several cancers, including those with a neuroendocrine phenotype. However, their impact on bronchopulmonary neuroendocrine neoplasms (BP-NENs) has not been investigated. The aim of this pilot study was to determine mRNA and protein levels of NEK2, PIM1, and PIM3 in a group of 49 patients with BP-NENs: 11 typical carcinoids, 5 atypical carcinoids, 11 large cell neuroendocrine carcinomas, 22 small cell lung carcinomas (SCLC). The expression was measured using TaqMan-based RT-PCR and immunohistochemistry. NEK2 and PIM1 mRNA levels were higher in the SCLC patients than in the other BP-NEN groups (p < 0.001). There was an association between NEK2 mRNA and protein expression (p = 0.023) and elevated NEK2 mRNA levels were related to reduced survival in BP-NEN patients (p = 0.015). Patients with higher PIM1 protein expression had also diminished survival comparing with those with weak or no PIM1 expression (p = 0.037). Elevated NEK2 and PIM1 expression were related to aggressive tumor phenotype and indirectly affected the overall survival of BP-NEN patients. Our pilot study supports the need for future investigation of the biological function of NEK2 and PIM1 in BP-NEN transformation to verify the clinical value of our findings.
Highlights
Neuroendocrine neoplasms (NENs) are rare malignancies arising from cells throughout the diffuse endocrine system, and their incidence has significantly risen in the last years
In the whole bronchopulmonary neuroendocrine neoplasms (BP-NEN) group, the highest mRNA level was determined for kinase PIM3 (RQ 2.34 (1.54–3.75)), which was higher than the PIM1 mRNA level (RQ 1.22 (0.66– 2.05))
The present study is the first to show that NEK2 and PIM1 expression is associated with BP-NEN aggressiveness
Summary
Neuroendocrine neoplasms (NENs) are rare malignancies arising from cells throughout the diffuse endocrine system, and their incidence has significantly risen in the last years. According to the 2015 World Health Organization (WHO) classification, bronchopulmonary neuroendocrine neoplasms (BP-NEN) comprise four tumor entities which differ with respect to their histology, mitotic count, and extent of necrosis: Endocr Pathol (2020) 31:264–273 typical carcinoids (TC), atypical carcinoids (AC), small cell lung cancers (SCLC), and large cell neuroendocrine carcinomas (LCNEC) [1]. TC and AC represent the welldifferentiated forms of BP-NENs named neuroendocrine tumors (NETs), while SCLC and LCNEC comprise poorly differentiated lung NENs called neuroendocrine carcinomas (NECs) [2]. The differences in the biology and clinical course of NET and NEC tumors entail distinct therapeutic approaches. The lack of relevant new therapeutic approaches in SCLC is in prominent contrast to personalized medicine for advanced stage non-small cell lung cancers (NSCLC), which benefits from targeted therapies and immunotherapy [8]
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