Class III/IV POU transcription factors expressed in small cell lung cancer cells are involved in proneural/neuroendocrine differentiation

Abstract

One-third of lung malignancies demonstrate a proneural/neuroendocrine phenotype or type of differentiation. However, it has not been clearly elucidated how proneural/neuroendocrine differentiation is controlled in lung cancers. We recently demonstrated that the POU3F2 gene plays a significant role in proneural/neuroendocrine differentiation of lung cancers. Because class III POU genes (POU3F1, POU3F2, POU3F3, and POU3F4) and class IV POU genes (POU4F1, POU4F2, and POU4F3) share similar properties in neural development, we analyzed the association between class III/IV POU genes and a proneural/neuroendocrine phenotype in lung cancers using seven small cell lung cancer (SCLC) cell lines and twelve non-SCLC (NSCLC) cell lines. Class III/IV POU gene expression was generally restricted to SCLC cells. However, the forced expression of class III/IV POU genes in the NSCLC cell lines induced the expression of neuroendocrine-specific markers (neural call adhesion molecule 1, synaptophysin, and chromogranin A) and proneural transcription factors (achaete-scute homolog-like 1, NeuroD1, and thyroid transcription factor 1) in various degrees. Furthermore, each class III/IV POU gene induced other class III/IV POU genes, suggesting the mutual induction of class III/IV POU genes. These findings suggest that the expression of class III/IV POU genes is important for the proneural/neuroendocrine differentiation of lung cancer cells.

Expression of developing neural transcription factors in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH)

“…The study drew on three cases of DIPNECH meeting the minimum pathologic criteria proposed by Marchevsky et al [15]: ≥3 bronchioles with ≥5 neuroendocrine cells (NECH) and ≥3 carcinoid tumorlets. Clinical data (gender, age at onset, smoking status, surgical procedure, and follow-up information) and pathological findings were retrieved from the hospital archives and retrospectively reviewed.…”

“…POU transcription factors play essential roles in organ development and cellular differentiation. POU-III/IV induce expression of neuroendocrine markers (synaptophysin, neural cell adhesion molecule 1, and chromogranin A), act as regulators of neuroendocrine differentiation in lung cancer cells, and are proneural transcription factors (ASCL1 and neuroD) [15,18].…”

“…TTF1 plays a crucial role in the morphogenesis of the thyroid gland, lung, and brain [12] by activating the synthesis of thyroglobulin, thyroperoxidase, thyrotropin receptor, and surfactant proteins and by repressing myosin binding protein H and the transforming growth factor-β, which inhibit cell migration and epithelial-tomesenchymal transition, respectively [13,14]. It is directly induced by POU3F2, FOXA1, FOXA2, POU3F4, and POU4F2 [7,15]. In the lung, it is frequently expressed by lung adenocarcinomas with terminal respiratory unit differentiation and by neuroendocrine tumors [7,16,17].…”

Recent advances in histogenesis research of lung neuroendocrine cancers: Evidence obtained from functional analyses of primitive neural/neuroendocrine cell‐specific transcription factors

“…TTF1 inhibits the transforming growth factor‐β‐mediated epithelial‐to‐mesenchymal transition in lung adenocarcinoma cells; moreover, myosin binding protein H, which inhibits cell migration through inhibitory interaction with Rho kinase 1, has been reported to be a transcriptional target of TTF1 . Recently, we reported that TTF1 is directly induced by POU3F2 (which is specifically expressed in SmCC cells), FOXA1, and FOXA2 and that POU3F4 and POU4F2 also strongly induce TTF1 expression . TTF1 is an important transcription factor for fetal diencephalon morphogenesis, and POU3F2 plays crucial roles in the development of the endocrine hypothalamus and posterior pituitary gland .…”

“…The class III POU transcription factors co‐localize and interact each other . We recently reported that all class III/IV POU transcription factors are specifically expressed in SmCC cells, in which they induce the expression of not only neuroendocrine markers (i.e., synaptophysin, neural cell adhesion molecule 1, and chromogranin A) but also proneural transcription factors (i.e., ASCL1 and ND1), and also mutually induce the other class III/IV transcription factors . Notably, POU3F4 and POU4F2 cause morphological changes (i.e., cytoplasmic miniaturization, spindle shaping, and thin cytoplasmic projection formation) in large cell lung carcinoma cells .…”