Abstract:
Pulmonary neuroendocrine (NE) cells are rare airway epithelial cells. The balance between Achaete-scute complex homolog 1 (ASCL1) and hairy and enhancer of split 1, one of the target molecules of the Notch signaling pathway, is crucial for NE differentiation. Small cell lung cancer (SCLC) is a highly aggressive lung tumor, characterized by rapid cell proliferation, a high metastatic potential, and the acquisition of resistance to treatment. The subtypes of SCLC are defined by the expression status of NE cell-lineage transcription factors, such as ASCL1, which roles are supported by SRY-box 2, insulinoma-associated protein 1, NK2 homeobox 1, and wingless-related integration site signaling. This network reinforces NE differentiation and may induce the characteristic morphology and chemosensitivity of SCLC. Notch signaling mediates cell-fate decisions, resulting in an NE to non-NE fate switch. The suppression of NE differentiation may change the histological type of SCLC to a non-SCLC morphology. In SCLC with NE differentiation, Notch signaling is typically inactive and genetically or epigenetically regulated. However, Notch signaling may be activated after chemotherapy, and, in concert with Yes-associated protein signaling and RE1-silencing transcription factor, suppresses NE differentiation, producing intratumor heterogeneity and chemoresistance. Accumulated information on the molecular mechanisms of SCLC will contribute to further advances in the control of this recalcitrant cancer.
摘要:
肺神经内分泌(NE)细胞是罕见的气道上皮细胞。Achaete-scute复合物同源物1(ASCL1)与Notch信号通路的靶分子之一split1的毛状和增强子之间的平衡,对NE分化至关重要。小细胞肺癌(SCLC)是一种高度侵袭性的肺癌,以快速细胞增殖为特征,高转移潜能,以及对治疗的抵抗力。SCLC的亚型由NE细胞谱系转录因子的表达状态定义。例如ASCL1,其作用由SRY-box2,胰岛素瘤相关蛋白1,NK2同源盒1和无翼相关的整合位点信号支持。该网络增强了NE分化,并可能诱导SCLC的特征性形态和化学敏感性。Notch信号介导细胞命运决定,导致NE到非NE的命运转变。NE分化的抑制可能会将SCLC的组织学类型改变为非SCLC形态。在具有NE分化的SCLC中,Notch信号传导通常是无活性的并且是遗传或表观遗传调节的。然而,Notch信号可能在化疗后被激活,and,与Yes相关蛋白信号和RE1沉默转录因子一致,抑制NE分化,产生肿瘤内异质性和化学耐药性。关于SCLC分子机制的累积信息将有助于控制这种顽固性癌症的进一步进展。