Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, 1600 Huron Parkway, Ann Arbor, MI, 48109, USA.
USC/Norris Comprehensive Cancer Center and Department of Pathology, Keck School of Medicine of USC, 1441 Eastlake Avenue, Los Angeles, CA, 90089, USA.
Sci Rep. 2020 Feb 7;10(1):2160. doi: 10.1038/s41598-020-59116-x.
Epithelial ovarian cancer (EOC) is a leading cause of cancer-related mortality in the United States due to the late-stage disease at diagnosis. Overexpression of GRP78 and PDI following endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) promote growth and invasion in cancer. To identify novel prognostic biomarkers in EOC, here we determined the expression of ER stress-associated proteins (GRP78, ATF6 and PERK) and correlated with clinical outcome in EOC. Tissue microarray (TMA) samples from 415 tissues collected from three cancer centers (UM, USC, and KCCRI) were used to assess the expression levels of ER-associated proteins using immunohistochemistry (IHC). We observed that the expression levels of GRP78 (p < 0.0001), ATF6 (p < 0.0001), and PERK (p < 0.0001) were significantly increased in specimens of EOC compared to normal tissues, including in the serous subtype (p < 0.0001). Previously we reported that high expression of PDI correlated with poor patient survival in EOC. Here we showed that overexpression of GRP78 and PDI protein expression correlated with poor patient survival (p = 0.03), while low expression of combined GRP78 and PDI correlated with better survival (p = 0.01) in high-grade serous. The increased expression of ER stress-associated proteins in EOC suggests a role for ER stress and the UPR in EOC. More importantly, our results demonstrate that GRP78 and PDI are potential biomarkers for EOC and could be used as dual prognostic markers.
上皮性卵巢癌（EOC）是美国癌症相关死亡的主要原因，这是由于诊断时疾病已处于晚期。内质网（ER）应激和未折叠蛋白反应（UPR）激活后，GRP78 和 PDI 的过表达促进了癌症的生长和侵袭。为了在 EOC 中确定新的预后生物标志物，我们在这里确定了 ER 应激相关蛋白（GRP78、ATF6 和 PERK）的表达，并与 EOC 的临床结果相关。使用免疫组织化学（IHC）从三个癌症中心（UM、USC 和 KCCRI）收集的 415 个组织的组织微阵列（TMA）样本评估 ER 相关蛋白的表达水平。我们观察到，与正常组织相比，EOC 标本中 GRP78（p<0.0001）、ATF6（p<0.0001）和 PERK（p<0.0001）的表达水平显着增加，包括浆液性亚型（p<0.0001）。我们之前报道过，PDI 的高表达与 EOC 患者的不良生存相关。在这里，我们表明 GRP78 和 PDI 蛋白表达的过表达与患者生存不良相关（p=0.03），而在高级别浆液性中，GRP78 和 PDI 联合低表达与更好的生存相关（p=0.01）。EOC 中 ER 应激相关蛋白的增加表达表明 ER 应激和 UPR 在 EOC 中起作用。更重要的是，我们的结果表明 GRP78 和 PDI 是 EOC 的潜在生物标志物，并且可以用作双重预后标志物。
