Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma

Abstract

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. Epithelial ovarian cancers (EOC) are a leading cause of death from gynecologic malignancies and the fifth most common cause of cancer deaths in the United States, in large part because they are typically diagnosed at late stage 1. Surgery and platinum/taxane-based chemotherapy form the mainstay of treatment 2. Despite relatively high initial response rates, the majority of patients with advanced disease unfortunately recur following first-line treatment 2,3. Previous studies showed that detection of the disease at an early stage is associated with prolonged survival, whereas patients diagnosed with advanced-stage EOC have significantly shorter survival rates 4-6. Thus, early detection is still regarded as an important, albeit elusive, criterion for successfully treating and optimizing survival for patients with EOC. The commonly used biomarker, CA-125, to detect EOC is neither sensitive nor specific enough for early detection of the disease 4. Hence, the discovery of new biomarkers is needed. The activation of the unfolded protein response (UPR) and overexpression of chaperone proteins, 78 kDa glucose-regulated protein (GRP78) and protein disulfide isomerase (PDI), following ER stress promotes growth, survival, and invasion 7-13. Cellular stress, due to the accumulation of misfolded/unfolded proteins, activates the UPR that halts the translation of proteins and stimulates the degradation of unfolded and aggregated proteins. Ultimately, the cell undergoes apoptosis unless protein homeostasis is restored 14. Thus, in the presence...

CREBBP knockdown suppressed proliferation and promoted chemo-sensitivity via PERK-mediated unfolded protein response in ovarian cancer

“…In EOC, GRP78, ATF6α and PERK were highly expressed in EOC tissues compared to the normal tissues, and correlated with advanced tumor stages. Moreover, high expression of GRP78 predicted poor overall survival (OS), suggesting that expression of UPR-associated proteins could be prognostic biomarkers in ovarian cancer [32]. Our study found that knockdown of CREBBP decreased GRP78 expression, suggesting low expression of CBP was correlated with good prognosis in ovarian cancer, which was in accordance with the results generated from the Kaplan-Meier Plotter database (Fig.…”

“…Emerging evidence showed that activation of UPR signaling contributed to tumor development and was correlated with unfavorable prognosis in cancer patients 31 , 32 . In EOC, GRP78, ATF6α and PERK were highly expressed in EOC tissues compared to the normal tissues, and correlated with advanced tumor stages.…”

Interplay between endoplasmic reticulum stress and non-coding RNAs in cancer

“…Due to the major pro-survival role of ATF6, its expression level has been shown to be significantly upregulated in various cancer types [63][64][65][66]. Higher expression level of ATF6 has been closely correlated with cancer metastasis and recurrence [67,68] and served as a prognostic indicator of cancer [69].…”

An Overview of Candidate Therapeutic Target Genes in Ovarian Cancer

“…Therefore, it is not surprising that hypoxia-dependent signaling pathways are commonly de-regulated in cancer cells. A recent study demonstrated that clear cell and serous EOC are under constant endoplasmic reticulum (ER) stress caused by the accumulation of unfolded proteins; due to this, the unfolded protein response (UPR) sensor PERK located in the ER activates and phosphorylates the eukaryotic translation initiation factor eIF2, resulting in a general suppression of translational initiation and global protein synthesis [ 117 ].…”