Neuron-specific enolase promotes stem cell-like characteristics of small-cell lung cancer by downregulating NBL1 and activating the BMP2/Smad/ID1 pathway

Abstract

Little is known about the biological functions of neuron-specific enolase (NSE) as a specific biomarker for small-cell lung cancer (SCLC). Herein, we elucidate the effect and mechanism of NSE on SCLC stem cell-like characteristics. Upregulated NSE expression was observed in spheroid cells. The gain-of-function and loss-of-function approaches demonstrated that modulation of NSE positively regulated cell proliferation, drug resistance, spherical clone formation, tumor growth, and stem cell-like characteristics of SCLC cells. Mechanistic studies revealed that NSE might downregulate the expression of neuroblastoma suppressor of tumorigenicity 1 (NBL1) by interacting with NBL1, thereby attenuating the competitive inhibitory effect of NBL1 on BMP2 and enhancing the interaction between BMP2 and BMPR1A; this, in turn, may activate the BMP2/Smad/ID1 pathway and promote SCLC stem cell-like characteristics. Moreover, overexpression of NBL1or knockdown of BMP2 rescued the NSE-induced stem cell-like characteristics. In clinical specimens, NSE expression was positively associated with ALDH1A1 expression and negatively correlated with NBL1 expression. High NSE and ALDH1A1 expressions and low NBL1 expression were correlated with poor prognosis in patients with SCLC. In summary, our study demonstrated that NSE promoted stem cell-like characteristics of SCLC via NBL1 and the activation of the BMP2/Smad/ID1 pathway.

Single‐cell transcriptome analysis reveals cellular and molecular alterations in small cell lung cancer tumors following chemotherapy

“…GO and KEGG enrichment analyses linked differential gene expression in stalk‐like cells to the functions of endothelial cells (such as fluid shear stress and regulation of angiogenesis) as well as initiation and development of tumors such as SCLC (Figure 3D‐F). For example, the differentially expressed gene ID1 has been shown to enhance angiogenesis and stem cell‐like characteristics of SCLC 23 . Vascular endothelium is exposed to fluid shear stress from blood flow, and such stress mediates the remodeling of existing blood vessels and development of new ones, which in turn influences risk of cancer metastasis.…”

“…For example, the differentially expressed gene ID1 has been shown to enhance angiogenesis and stem cell-like characteristics of SCLC. 23 Vascular endothelium is exposed to fluid shear stress from blood flow, and such stress mediates the remodeling of existing blood vessels and development of new ones, which in turn influences risk of cancer metastasis. Silencing of CAV1, which was linked to fluid shear stress in our study, increases sensitivity of nonsmall cell lung cancer to cisplatin-induced apoptosis.…”

Association between PET-CT accumulation in the hypothalamic /pituitary regions and neuron-specific enolase /primary tumor in limited-stage small cell lung cancer

“…However, a sub-analysis reported that it was not a prognostic factor in the group that underwent chemotherapy or surgery plus chemotherapy [20]. NSEs have been reported to promote cancer stem cell-like properties for small cell lung cancer [21].…”

Association between PET–CT accumulation in the hypothalamic/pituitary regions and neuron-specific enolase/primary tumor in limited-stage small cell lung cancer: a case-controlled retrospective study

“…However, a sub-analysis reported that NSE was not a prognostic factor in the group that underwent chemotherapy or surgery plus chemotherapy (Tian et al 2020 ). NSEs have been reported to promote cancer stem cell-like properties in small cell lung cancer (Lu et al 2022 ). These results suggest that NSE is a prognostic factor in the limited stage (Lu et al 2022 ).…”