ABSTRACT: Background. 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).

Methods. 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.

Results. In patients with HNSCC, high LAMP3 expression correlated with

N classification (p 5 .019) and the occurrence of distant metastases

during follow-up (p 5 .039). Patients with high LAMP3 levels had a

worse metastasis-free survival (p 5 .008). Intriguingly, LAMP3 expression

was localized exclusively in normoxic areas of tumors and

xenografts. Expression of PERK, p-PERK, p-eIF2a, ATF4, and LAMP3

was not universally induced in hypoxic HNSCC cell lines. Exposure to

endoplasmic reticulum-stress stimulated PERK, ATF4, and LAMP3

expression.

Conclusion. 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.