Elevated GRP78 expression is associated with poor prognosis in patients with pancreatic cancer

Abstract

Glucose-regulated protein 78 (GRP78) is a member of the heat-shock protein 70 family. We evaluated the expression of GRP78 using tissue microarray-based immunohistochemistry in tumor tissues and adjacent nontumor tissues from 180 pancreatic ductal adenocarcinoma (PDAC) patients. The associations between the expression levels of GRP78, clinicopathological factors, and overall survival were evaluated. The results showed that the expression of GRP78 was significantly higher in PDAC cells than in normal pancreatic duct cells within adjacent nontumor tissues (p < 0.05). The increased expression of GRP78 in the tumor tissues was significantly correlated with a higher T-stage (p < 0.05) and a shorter overall survival (OS, p < 0.05). In an in vitro study, the regulation of GRP78 in the PDAC cell lines affected the proliferation, migration, and invasion of PDAC cells through the regulation of CyclinD1, cyclin-dependent kinase (CDK) 4, CDK6, phospho-signal transducer, activator of transcription 3 (p-STAT3), janus kinase 2 (JAK2), ras homolog gene family member A (RhoA), Rho-associated kinase 1 (ROCK1), and sterile alpha motif domain containing protein 4 (Smad4). The present data suggest that GRP78 plays a crucial role in the proliferation, migration, and invasion of pancreatic cancer cells and may be a suitable prognostic marker in PDAC.

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

“…Furthermore, GRP78 was upregulated in ductal structures of both human and murine ADM and PDAC lesions and colocalized with activated AKT on the cell surface (26). In human PDAC cell lines, knockdown of GRP78 or treatment of the cells with anti-GRP78 agents resulted in decreased proliferation, invasion, viability, and chemoresistance, suggesting that suppression of GRP78 could represent a novel approach to combat human mutant KRAS-driven PDAC (14,25,27,28).…”

“…A high level of GRP78 was detected by mass spectrometry imaging and immunohistochemistry (IHC), as well as proteomic and tissue microarray profiling of microdissected pancreatic cancer nests and was associated with poor prognosis and shorter overall survival (23)(24)(25). Furthermore, GRP78 was upregulated in ductal structures of both human and murine ADM and PDAC lesions and colocalized with activated AKT on the cell surface (26).…”

GRP78‐mediated antioxidant response and ABC transporter activity confers chemoresistance to pancreatic cancer cells

“…Additionally, we found GRP78 to be overexpressed in the ducts/pseudoducts of patient biopsy punches, which is consistent with recently published studies (Fig. 1E) (Gifford et al ., 2016; Niu et al ., 2015). …”

“…XBP1s also correlates with higher tumor grade, chemoresistance, and shorter survival in lymphoma (Wang and Kaufman, 2014). GRP78, the regulator of the UPR, has previously been correlated with poor patient prognosis in multiple cancers, including pancreatic cancer (Avril et al ., 2017; Gifford et al ., 2016; Ma and Hendershot, 2004; Niu et al ., 2015; Wang and Kaufman, 2014). Based on correlation studies and direct overexpression leading to chemoresistance, numerous proteins in the UPR pathway have been targeted with small molecules in hopes to attenuate chemoresistance (Chevet et al ., 2015; Gifford et al ., 2016; Lee, 2014; Roller and Maddalo, 2013).…”

“…It was recently reported that GRP78 correlates with poor prognosis and chemoresistance in pancreatic cancer (Gifford et al ., 2016; Niu et al ., 2015). Further, it was shown that gemcitabine‐resistant cell lines have higher GRP78 expression compared to gemcitabine‐sensitive cell lines (Gifford et al ., 2016).…”