ASCL1 and RET expression defines a clinically relevant subgroup of lung adenocarcinoma characterized by neuroendocrine differentiation

Abstract

ASCL1 is an important regulatory transcription factor in pulmonary neuroendocrine (NE) cell development, but its value as a biomarker of NE differentiation in lung adenocarcinoma (AD) and as a potential prognostic biomarker remains unclear. We examined ASCL1 expression in lung cancer samples of varied histologic subtype, clinical outcome and smoking status and compared with expression of traditional NE markers. ASCL1 mRNA expression was found almost exclusively in smokers with AD, in contrast to non-smokers and other lung cancer subtypes. ASCL1 protein expression by immunohistochemical (IHC) analysis correlated best with synaptophysin compared with chromogranin and CD56/NCAM. Analysis of a compendium of 367 microarray-based gene expression profiles in stage I lung adenocarcinomas identified significantly higher expression levels of the RET oncogene in ASCL1-positive tumors (ASCL1+) compared with ASCL1− tumors (q-value <10−9). High levels of RET expression in ASCL1+ but not in ASCL1− tumors was associated with significantly shorter overall survival (OS) in stage 1 (P = 0.007) and in all AD (P = 0.037). RET protein expression by IHC had an association with OS in the context of ASCL1 expression. In silico gene set analysis and in vitro experiments by ASCL1 shRNA in AD cells with high endogenous expression of ASCL1 and RET implicated ASCL1 as a potential upstream regulator of the RET oncogene. Also, silencing ASCL1 in AD cells markedly reduced cell growth and motility. These results suggest that ASCL1 and RET expression defines a clinically relevant subgroup of ∼10% of AD characterized by NE differentiation.

Shutdown of Achaete-scute Homolog-1 Expression by Heterogeneous Nuclear Ribonucleoprotein (hnRNP)-A2/B1 in Hypoxia

“…It is overexpressed in a variety of tumors, including breast, lung, and pancreas carcinomas (51)(52)(53). Altered expression of hnRNP-A2/B1 has also been reported during lung carcinogenesis where hASH1 seems to be involved (54,55). Histochemical mapping of hnRNP-A2/B1 suggested a function in post-transcriptional regulation of neurons in the cerebral cortex and hippocampus in response to ischemia-reperfusion injury (56).…”

NETest Liquid Biopsy Is Diagnostic of Lung Neuroendocrine Tumors and Identifies Progressive Disease

“…A minority (10%) of ACC exhibited NETest levels > 40%. This may reflect the well-described phenomenon of neuroendocrine differentiation in highly aggressive lung tumors [36, 37] and likely detects a tissue-­derived neuroendocrine phenotype. Recent publications have identified significant cellular heterogeneity in lung neoplasia including NE differentiation in ∼10% of ACC and reclassification of 5% of SCCs as LCNEC [36, 38, 39].…”

Achaete-scute complex homologue-1 promotes development of laryngocarcinoma via facilitating the epithelial–mesenchymal transformation

“…This result is consistent with that of the research of lung adenocarcinoma. 5 Additionally, ASCL1 was overexpressed in laryngeal cancer with high migration level, but profoundly expressed weakly in laryngeal cancer with low migration level, suggesting that ASCL1 may be of a tumor-accelerating property. 24 Besides, multivariate analysis showed that ASCL1 protein was an important independent prognostic factor for overall survival, and ASCL1 could be used as a new predictor of the prognosis of cases with laryngeal cancer.…”

“…5 Some studies indicated that the abnormal expression and function of ASCL1 protein are crucial to the occurrence of human cancers [6][7][8][9][10][11][12] of many kinds, in which increased ASCL1 expression levels have been detected, and silencing ASCL1 expression could suppress the proliferation of both cancer 6,7,10 and neuroendocrine tumor. 5,13,14 And some report that suppression of ASCL1 expression by RNA interference could lead to cellcycle procession as well as cell differentiation and apoptosis and inhibit growth in vitro in an ASCL1 expression-dependent manner. 11,15,16 It was found that ASCL1 is also involved in the migration of cancer cells in various carcinoma cell lines such as oral squamous cell carcinoma line 17 and lung cancer cell lines.…”