Expression of protein disulfide isomerase family members correlates with tumor progression and patient survival in ovarian cancer

Samanta, Soma; Tamura, Shuzo; Dubeau, Louis; Mhawech‐Fauceglia, Paulette; Miyagi, Yohei; Kato, Hiroyuki; Lieberman, Richard W.; Buckanovich, Ronald J.; Lin, Yvonne G.; Neamati, Nouri

doi:10.18632/oncotarget.21569

Cited by 45 publications

(38 citation statements)

References 47 publications

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“…The Kaplan-Meier survival analysis method was used to generate survival curves using low (<median expression) and high expression (>median expression) groups. For the PDI survival curve, part of the data was used in previously published article 25 . (2020) 10:2160 | https://doi.org/10.1038/s41598-020-59116-x www.nature.com/scientificreports www.nature.com/scientificreports/ showed prognostic value in cancers.…”

Section: Discussionmentioning

confidence: 99%

“…Immunohistochemistry and automated analysis of immunohistochemistry. Immunohistochemical (IHC) staining was performed by the Pathology Core at the University of Michigan as previously described 25 . Briefly, IHC staining was used to assess protein expression on TMA slides.…”

Section: Discussionmentioning

confidence: 99%

“…Like GRP78, PDI also has a dual role in cell death and survival during ER stress. Previously, we demonstrated that PDI is a potential biomarker for EOC 25 . GRP78 has also been reported as a potential independent predictor of recurrence and survival in prostate cancer 26 and of responsiveness to chemotherapy in breast cancer 27 .…”

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confidence: 98%

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Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma

Samanta

Tamura

Dubeau

et al. 2020

Sci Rep

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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...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma

Samanta

Tamura

Dubeau

et al. 2020

Sci Rep

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“…Herein, we evaluated the expression pro le of PDIA6 in OSCC tissues using qPCR and western blotting assays, and found that PDIA6 expression level was apparently increased in OSCC tissues. PDIA6 expression pattern in OSCC was consistent with NSCLC (15), bladder cancer (16), ovarian cancer (21) and hepatocellular carcinoma (17). Further analysis showed that higher level of PDIA6 in OSCC patients was closely associated with lower overall survival, higher TNM stage (p = 0.006), poorer tissue differentiation (p = 0.036) and perineural invasion (p = 0.034).…”

Section: Discussionmentioning

confidence: 54%

PDIA6 Contributes to Aerobic Glycolysis and Cancer Progression in Oral Squamous Cell Carcinoma

Mao

Gong

et al. 2020

Preprint

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Background/Objective: Accumulated evidence has demonstrated that aerobic glycolysis serves as a regulator of tumor cell growth, invasion and angiogenesis. Herein, we explored the role of protein disulfide isomerase family 6 (PDIA6) in the aerobic glycolysis and the progression of oral squamous cell carcinoma (OSCC). Methods: The expression pattern of PDIA6 in OSCC tissues was determined by qPCR and western blotting. Lentivirus and small interfering RNAs (siRNAs) were introduced into cells to upregulate and downregulate PDIA6 expression. CCK-8, flow cytometry, transwell and xenotransplantation models were applied to detect cell proliferation, apoptosis, migration, invasion and tumorigenesis, respectively. Results: A high expression pattern of PDIA6 was observed in OSCC tissues, which was closely associated with lower overall survival and malignant clinical features in OSCC. Compared with the control group, overexpression of PDIA6 induced significant enhancements in cell growth, migration, invasiveness and tumorigenesis and decreased cell apoptosis, while knockdown of PDIA6 caused opposite results. In addition, overexpression of PDIA6 increased glucose consumption, lactate production and ATP level in OSCC cells.Conclusion: This study demonstrated that PDIA6 expression was elevated in OSCC tissues, and overexpression of it promoted OSCC progression and aerobic glycolysis.

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“…The ectopic expression and function of PDIA4 had also been reported in ovarian cancer. In ovarian carcinoma, PDIA4 was found to take part in the drug-resistance phenotype and can serve as a critical prognostic marker [19,20]. Moreover, in pancreatic carcinoma, hepatocellular carcinoma and esophageal squamous cell carcinoma, the increased expression of PDIA4 was respectively observed and associated with tumor development [21][22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

PDIA4 correlates with poor prognosis and is a potential biomarker in glioma

Liu

Xiao

et al. 2020

Preprint

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Background: Gliomas, characterized by aggressiveness and invasiveness, remain incurable after conventional therapies. The molecular mechanisms driving the progression and maintenance of glioma are still poorly understood.Methods: PDIA4 expression was analyzed via Gene Expression Profiling Interactive Analysis (GEPIA) which data were from TCGA and GTEx databases. We estimated the prognostic value of PDIA4 using Kaplan–Meier survival analysis and the Cox proportional hazard model. The functional enrichment analysis was done by using cluster Profiler package in R language, including gene ontology (GO) analysis comprised of cellular component (CC), molecular function (MF), and biological process (BP), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. In addition, correlation between PDIA4 and immunity were analyzed by Protein-protein interaction (PPI) analysis, RNA extraction and Real-time RT-PCR.Results: In this study, we identified PDIA4 was highly expressed in gliomas and closely correlated with poor prognosis. The association with IDH1 and different patterns of gliomas also indicates the potential biological processes that PDIA4 involves in the development of tumor. Mechanistically, PDIA4 interacts with multiple immunological components to promote an immunosuppressive tumor microenvironment (TME).Conclusions: Our results confirm PDIA4 is an efficient biomarker of gliomas, with implications for prognosis and therapeutic strategies.

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Expression of protein disulfide isomerase family members correlates with tumor progression and patient survival in ovarian cancer

Cited by 45 publications

References 47 publications

Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma

Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma

PDIA6 Contributes to Aerobic Glycolysis and Cancer Progression in Oral Squamous Cell Carcinoma

PDIA4 correlates with poor prognosis and is a potential biomarker in glioma

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