Overexpression of MYCN promotes proliferation of non-small cell lung cancer

Abstract

V-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) is an oncogene that is known amplified and overexpressed in different human malignancies including small cell lung cancer. However, the role of MYCN in non-small cell lung cancer (NSCLC) development remains elusive. In the present study, Western blot and immunohistochemistry assays demonstrated that MYCN was overexpressed in NSCLC tumor tissues and cell lines. In addition, immunohistochemistry analysis revealed that upregulation of MYCN expression was positively correlated with a more invasive tumor phenotype and poor prognosis. In vitro studies using serum starvation-refeeding experiment and MYCN-siRNA transfection assay demonstrated that MYCN expression promoted proliferation of NSCLC cells, while MYCN knockdown led to decreased cell growth resulted from growth arrest of cell cycle at G0/G1 phase. Furthermore, upregulation and knockdown of sex-determining region Y-box 2 (SRY) (SOX2), which was a well-known oncogene, confirmed that MYCN might be a downstream gene of the transcription factor SOX2. Collectively, our finding suggested that MYCN might contribute to the progression of NSCLC by enhancing cell proliferation, and that targeting MYCN might provide beneficial effects for the clinical therapy of NSCLC.

The MYCN Protein in Health and Disease

“…When the gene is mutated to a null allele or a conditional knock out in utero, there is a reduction in lung growth and reduced branching [6]. Lung cancer is one of the most common cancers in the world [182,183]. Along with p53 and RB1 genomic alterations, amplification of the MYC family is observed in 20%–40% of small cell lung cancer (SCLC) cases [167,182,184,185].…”

“…As with prostate cancer, AURKA has been linked to the disease but its inhibition does not alter MYCN levels, suggesting a difference in activity in MYCN -amplified non-small lung cancer cells (NSCLC) compared to MYCN -amplified neuroblastoma and prostate cancer [184]. Other targets of the MYCN pathway such as SOX2, p53, miR-34a and miR-9, have been proposed to affect the poor prognosis of NSCLC [182,183,187]. SOX2, a transcription factor involved in differentiation, proliferation and apoptosis, has been shown to be frequently amplified in NSCLC.…”

“…SOX2, a transcription factor involved in differentiation, proliferation and apoptosis, has been shown to be frequently amplified in NSCLC. High expression of MYCN correlates with SOX2 expression, suggesting that their activity is linked, but further investigation is required [183]. MYCN has been proposed to drive cell death in part through p53 [147,159,182].…”

The clinical value of miR‐193a‐3p in non‐small cell lung cancer and its potential molecular mechanism explored in silico using RNA‐sequencing and microarray data

“…An increase in CDC25A expression by means of a decrease in miR‐184 promoted cell invasive capacity . MYCN was found to be overexpressed in NSCLC, which was positively related to a more invasive tumor phenotype and poorer outcome . AURKA functioned as an oncogene, and its low expression level inhibited tumor cell proliferation, promoted apoptosis and hindered cell cycle development in NSCLC .…”

Histopathological and molecular features of lung cancer

“…In addition, inactivating mutations in NOTCH family genes have been identified by whole-genome sequencing in 25% of human SCLC tumors, suggesting that these alterations may represent a major feature of SCLC (25) . NOTCH signaling is critical in the regulation of the neuroendocrine compartment size in the maturaation of lung and its inactivation could therefore contribute to malignant transformation of neuroendocrine cells (2,(27)(28)(29)(30) .…”