Nagelkerke Anika, Sweep Fred C G J, Stegeman Hanneke, Grénman Reidar, Kaanders Johannes H A M, Bussink Johan, Span Paul N
Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Head Neck. 2015 Jun;37(6):896-905. doi: 10.1002/hed.23693. Epub 2014 Jun 27.
The purpose of this study was to examine the hypoxic regulation of the PKR-like endoplasmic reticulum kinase (PERK)/activating transcription factor-4 (ATF4)/lysosome-associated membrane protein 3 (LAMP3)-arm of the unfolded protein response (UPR) in head and neck squamous cell carcinoma (HNSCC).
LAMP3 expression was determined in patient biopsies by immunohistochemistry and correlated to clinicopathological parameters. mRNA and protein expression for PERK, ATF4, and LAMP3 was evaluated after hypoxic exposure of HNSCC cell lines.
In patients with HNSCC, high LAMP3 expression correlated with N classification (p = .019) and the occurrence of distant metastases during follow-up (p = .039). Patients with high LAMP3 levels had a worse metastasis-free survival (p = .008). Intriguingly, LAMP3 expression was localized exclusively in normoxic areas of tumors and xenografts. Expression of PERK, p-PERK, p-eIF2α, ATF4, and LAMP3 was not universally induced in hypoxic HNSCC cell lines. Exposure to endoplasmic reticulum-stress stimulated PERK, ATF4, and LAMP3 expression.
LAMP3 is relevant for prognosis in HNSCC. However, the PERK/ATF4/LAMP3-arm of the UPR responds differently to hypoxia in HNSCC compared to other tumor types.
本研究旨在探讨头颈部鳞状细胞癌（HNSCC）中未折叠蛋白反应（UPR）的蛋白激酶R样内质网激酶（PERK）/激活转录因子4（ATF4）/溶酶体相关膜蛋白3（LAMP3）分支的缺氧调节。
通过免疫组织化学测定患者活检组织中的LAMP3表达，并将其与临床病理参数相关联。对HNSCC细胞系进行缺氧暴露后，评估PERK、ATF4和LAMP3的mRNA和蛋白表达。
在HNSCC患者中，高LAMP3表达与N分级（p = 0.019）以及随访期间远处转移的发生相关（p = 0.039）。LAMP3水平高的患者无转移生存期较差（p = 0.008）。有趣的是，LAMP3表达仅定位于肿瘤和异种移植的常氧区域。在缺氧的HNSCC细胞系中，PERK、p-PERK、p-eIF2α、ATF4和LAMP3的表达并非普遍诱导。内质网应激刺激可诱导PERK、ATF4和LAMP3表达。
LAMP3与HNSCC的预后相关。然而，与其他肿瘤类型相比，UPR的PERK/ATF4/LAMP3分支在HNSCC中对缺氧的反应不同。
