Shinmura Kazuya, Kato Hisami, Kawasaki Hideya, Hariyama Takahiko, Yoshimura Kimio, Tsuchiya Kazuo, Watanabe Hirofumi, Ohta Isao, Asahina Eri, Sumiyoshi Fumiya, Hamada Keisuke, Kawanishi Yuichi, Kawase Akikazu, Funai Kazuhito, Sugimura Haruhiko
Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Lab Invest. 2023 Feb;103(2):100007. doi: 10.1016/j.labinv.2022.100007. Epub 2023 Jan 10.
Most human malignant neoplasms show loss of primary cilia (PC). However, PC are known to be retained and involved in tumorigenesis in some types of neoplasms. The PC status in lung carcinomas remains largely uninvestigated. In this study, we comprehensively assessed the PC status in lung carcinomas. A total of 492 lung carcinomas, consisting of adenocarcinomas (ACs) (n = 319), squamous cell carcinomas (SCCs) (n = 152), and small cell lung carcinomas (SCLCs) (n = 21), were examined by immunohistochemical analysis using an antibody against ARL13B, a marker of PC. The PC-positive rate was markedly higher in SCLCs (81.0%) than in ACs (1.6%) and SCCs (7.9%). We subsequently performed analyses to characterize the PC-positive lung carcinomas further. PC-positive lung carcinomas were more numerous and had longer PC than normal cells. The presence of PC in these cells was not associated with the phase of the cell cycle. We also found that the PC were retained even in metastases from PC-positive lung carcinomas. Furthermore, the hedgehog signaling pathway was activated in PC-positive lung carcinomas. Because ARL13B immunohistochemistry of lung carcinoids (n = 10) also showed a statistically significantly lower rate (10.0%) of PC positivity than SCLCs, we searched for a gene(s) that might be upregulated in PC-positive SCLCs compared with lung carcinoids, but not in PC-negative carcinomas. This search, and further cell culture experiments, identified HYLS1 as a gene possessing the ability to regulate ciliogenesis in PC-positive lung carcinomas. In conclusion, our findings indicate that PC are frequently present in SCLCs but not in non-SCLCs (ACs and SCCs) or lung carcinoids, and their PC exhibit various specific pathobiological characteristics. This suggests an important link between lung carcinogenesis and PC.
大多数人类恶性肿瘤表现出原发性纤毛（PC）缺失。然而，已知在某些类型的肿瘤中，PC会保留并参与肿瘤发生。肺癌中的PC状态在很大程度上仍未得到研究。在本研究中，我们全面评估了肺癌中的PC状态。通过使用抗ARL13B（一种PC标志物）的抗体进行免疫组织化学分析，对总共492例肺癌进行了检查，其中包括腺癌（AC）（n = 319）、鳞状细胞癌（SCC）（n = 152）和小细胞肺癌（SCLC）（n = 21）。小细胞肺癌的PC阳性率（81.0%）明显高于腺癌（1.6%）和鳞状细胞癌（7.9%）。随后，我们进行了分析以进一步表征PC阳性肺癌。PC阳性肺癌比正常细胞数量更多且PC更长。这些细胞中PC的存在与细胞周期阶段无关。我们还发现，即使在PC阳性肺癌的转移灶中，PC也会保留。此外，在PC阳性肺癌中，刺猬信号通路被激活。由于对10例肺类癌进行的ARL13B免疫组织化学分析显示，PC阳性率（10.0%）在统计学上也显著低于小细胞肺癌，因此我们寻找了一个或多个基因，这些基因在PC阳性小细胞肺癌中可能上调，而在肺类癌中不上调，在PC阴性癌中也不上调。通过此次搜索以及进一步的细胞培养实验，确定HYLS1是一个具有调节PC阳性肺癌纤毛发生能力的基因。总之，我们的研究结果表明，PC在小细胞肺癌中经常存在，但在非小细胞肺癌（腺癌和鳞状细胞癌）或肺类癌中不存在，并且它们的PC表现出各种特定的病理生物学特征。这表明肺癌发生与PC之间存在重要联系。
