Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Cell Signal. 2018 Jun;46:83-91. doi: 10.1016/j.cellsig.2018.02.014. Epub 2018 Mar 1.
Neuroendocrine (NE) lung tumors account for 20% of total lung cancer cases and represent a subset of aggressive tumors with metastatic potential. High-risk NE lung cancer patients display disseminated disease, N-myc expression/amplification, and poorly differentiated tumors. In this study, we investigate the molecular mechanisms underlying a zinc-finger transcription factor, INSM1 in NE lung cancer. Our study revealed that INSM1 crosstalk with the Shh-PI3K/AKT-N-myc/Ascl1-MEK/ERK transcriptional network in NE lung cancer. The INSM1 expression pattern and functional data demonstrated that INSM1 is not only critical for NE differentiation, but also served as a NE tumor-specific marker in small cell lung carcinoma (SCLC). The Shh signaling pathway activates INSM1 expression through N-myc and Ascl1 in aggressive SCLC. The E2-box in the INSM1 promoter is the direct target recognized by N-myc and Ascl1 transcription factors. N-myc or Ascl1 activates endogenous INSM1 expression in lung cancer cells. INSM1 functions as a key player in NE lung cancer via Shh signaling that crosstalk with PI3K/AKT and MEK/ERK pathway to enhance N-myc stability in NE lung cancer. We investigate the negative effects of Shh inhibitor and knockdown of INSM1 in NE lung cancer cells. The combination of different Shh signaling pathway inhibitors targeting INSM1 and N-myc inhibits lung cancer cell growth and could be used as a new treatment option for SCLC.
神经内分泌（NE）肺肿瘤占肺癌总数的 20%，代表了具有转移潜能的侵袭性肿瘤亚群。高危 NE 肺癌患者表现为播散性疾病、N-myc 表达/扩增和低分化肿瘤。在这项研究中，我们研究了锌指转录因子 INSM1 在 NE 肺癌中的分子机制。我们的研究表明，INSM1 与 Shh-PI3K/AKT-N-myc/Ascl1-MEK/ERK 转录网络在 NE 肺癌中相互作用。INSM1 的表达模式和功能数据表明，INSM1 不仅对 NE 分化至关重要，而且在小细胞肺癌（SCLC）中也是 NE 肿瘤特异性标志物。Shh 信号通路通过 N-myc 和 Ascl1 在侵袭性 SCLC 中激活 INSM1 的表达。INSM1 启动子中的 E2 盒是 N-myc 和 Ascl1 转录因子识别的直接靶标。N-myc 或 Ascl1 在肺癌细胞中激活内源性 INSM1 表达。INSM1 通过与 PI3K/AKT 和 MEK/ERK 途径相互作用的 Shh 信号传导，在 NE 肺癌中作为关键参与者发挥作用，以增强 NE 肺癌中 N-myc 的稳定性。我们研究了 Shh 抑制剂和 INSM1 在 NE 肺癌细胞中的敲低的负效应。针对 INSM1 和 N-myc 的不同 Shh 信号通路抑制剂的组合抑制肺癌细胞生长，可作为 SCLC 的新治疗选择。
