Concomitant high expression of ERα36, GRP78 and GRP94 is associated with aggressive papillary thyroid cancer behavior

Non-small-cell lung cancer (NSCLC) represents most of lung cancers, is often diagnosed at an advanced metastatic stage. Therefore, exploring the mechanisms underlying metastasis is key to understanding the development of NSCLC. The expression of B cell receptor-associated protein 31 (BCAP31), calreticulin, glucose-regulated protein 78, and glucose-regulated protein 94 were analyzed using immunohistochemical staining of 360 NSCLC patients. It resulted that the high-level expression of the four proteins, but particularly BCAP31, predicted inferior overall survival. What's more, BCAP31 was closely associated with histological grade and p53 status, which was verified by seven cohorts of NSCLC transcript microarray datasets. Then, three NSCLC cell lines were transfected to observe behavior changes BCAP31 caused, we found the fluctuation of BCAP31 significantly influenced the migration, invasion of NSCLC cells. To identify the pathway utilized by BCAP31, Gene Set Enrichment Analysis was firstly performed, showing Akt/m-TOR/p70S6K pathway was the significant one, which was verified by immunofluorescence, kinase phosphorylation and cellular behavioral observations. Finally, the data of label-free mass spectroscopy implied that BCAP31 plays a role in a fundamental biological process. This study provides the first demonstration of BCAP31 as a novel prognostic factor related to metastasis and suggests a new therapeutic strategy for NSCLC.Lung cancer is one of the most prevalent neoplasms and the leading cause of cancer-related death worldwide, being responsible for nearly one in five cases 1 . Non-small-cell lung cancer (NSCLC) contributes to 85% of lung cancer cases. Owing to the absence of clinical symptoms and effective screening programs, most lung cancers are diagnosed at an advanced stage with metastasis. Targeted immunotherapy, including anti-angiogenic and checkpoint monoclonal antibodies or tyrosine kinase inhibitors, demonstrates better efficacy than traditional surgical treatment and radio-chemotherapy, although drug resistance and tumor heterogeneity remain significant problems, and metastasis remains the major cause of mortality 2 .It is therefore important to identify efficient symbolic markers of metastasis and therapeutic targets for NSCLC. Given the aberrant expression of specific genes in a variety of cancer types, restricted in testis or selected in normal tissue, cancer-testis antigens (CTAs) have emerged as efficient specific tumor targets which spare normal tissue from incurring damage during treatment 3 . Originally described in patients with malignant melanoma 4 , CTAs have been identified as biomarkers for a diverse range of cancers, including NSCLC 5 . Their expression is often coordinated 6 , and associated with poor clinical outcome 7 and advanced stage 8 , particularly metastasis 9 .with histological grade (p = 0.0009) and p53 status (p = 0.0058; Supplementary Table S1). However, there was no correlation between BCAP31 mRNA expression and NSCLC prognosis, which was inconsistent with our protein ...

Section: Discussionmentioning

confidence: 99%

BCAP31, a cancer/testis antigen-like protein, can act as a probe for non-small-cell lung cancer metastasis

Wang

Jiang

et al. 2020

Sci Rep

“…GRP78 is encoded by HSPA5, as the most abundant protein of heat shock protein-70 (Hsp70) family, mainly exits in ER lumen, corrects the folding and assembly, as well as prevents the transport of misfolded proteins or protein subunits [29,30]. GRP78 works as a molecular chaperone in cells, its high expression is crucial for proliferation, invasion, metastasis of many cancers, proves to be correlated with tumor resistance, recurrence, and a low OS [17,18,[31][32][33]. With the help of GRP78, tumor cells can organize the stimulation of processes including macroautophagy, combat reactive oxygen species (ROS), and activate pro-survival signaling pathways [29].…”

Section: Discussionmentioning

confidence: 99%

Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastric Cancer

Zhao

et al. 2020

Preprint

Background: Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) are represent for poor prognosis of various cancers. However, rare research investigate the correlation of them in cancer. This study aimed to investigate the correlation and prognostic value of P4HB and GRP78 expression along with clinical features in gastric cancer (GC).Methods: A total of 150 GC tissue samples separately evaluated P4HB and GRP78 protein expression by immunohistochemistry. Association of P4HB and GRP78 expression with clinicopathological features was analyzed. Bioinformatics analyses were performed to find correlation between mRNAs and pathways. Kaplan-Meier analyses were taken to compare survival curves. Univariate and multivariate Cox regression models used to analyze the impact of prognostic factors on overall survival (OS). A prognostic nomogram was constructed based on the multivariate Cox regression model, and compared to TNM stage in discrimination ability and clinical usefulness.Results: P4HB and GRP78 expression were both associated with tumor invasion and lymph node metastasis. P4HB protein positively correlated with GRP78, as well as the same tendency of mRNAs in both GC tissue and cell databases. Bioinformatics analyses indicated that P4HB and GRP78 may be associated with protein folding and response to ER stress, and the protein processing in ER pathway. High single or co-expression of P4HB and GRP78 represented for a shorter OS. When stratified by postoperative adjuvant chemotherapy, the high co-expression was only related to unfavorable prognosis of with chemotherapy group, especially in advanced stage. Multivariate Cox regression analysis identified co-expression of P4HB and GRP78 as an independent prognostic factor for OS. The nomogram including the co-expression was better than TNM stage in discrimination ability and clinical usefulness through the receiver operating characteristic (ROC) and decision curve analysis (DCA) curves.Conclusion: P4HB was positively correlated with GRP78 expression, co-expression of them was an independent prognostic factor, could serve as a predictive marker for GC patients with postoperative adjuvant chemotherapy in advanced stage.

“…GRP78 is encoded by HSPA5, as the most abundant protein of heat shock protein-70 family, mainly exits in ER lumen, prevents the transport of misfolded proteins or protein subunits, expect for correcting the folding and assembly [29,30]. GRP78 works as a molecular chaperone in cells, whose high expression is crucial for proliferation, invasion, metastasis of many cancers, proves to be correlated with tumor resistance, recurrence, and a low OS [17,18,[31][32][33]. With the help of GRP78, tumor cells can organize the stimulation of processes including combat reactive oxygen species, macroautophagy, and enable prosurvival signaling pathways [29].…”

Section: Discussionmentioning

confidence: 99%

Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastric Cancer

Zhao

et al. 2020

Preprint

Background: Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) represent for poor prognosis of various cancers, while rare research investigate correlation of them. This study aimed to explore the correlation and prognostic value of P4HB and GRP78 expression combined with clinical features in gastric cancer (GC).Methods: 150 GC tissue samples evaluated P4HB and GRP78 protein expression by immunohistochemistry separately. Association of the expression with clinicopathological features was analyzed. To explore correlation between their mRNAs and pathways, bioinformatics analyses were performed. Kaplan-Meier analyses were taken to compare survival curves. Univariate and multivariate Cox regression models were used to analyze potential prognostic factors of overall survival (OS). Basing on the multivariate Cox regression model, a prognostic nomogram was constructed, discrimination ability and clinical usefulness of which were compared to TNM stageResults: P4HB and GRP78 expression were both associated with tumor invasion and lymph node metastasis. P4HB protein positive correlated with GRP78, as the same tendency of mRNAs in both GC tissue and cell databases. Bioinformatics analyses indicated that P4HB and GRP78 may be associated with protein folding and response to ER stress, as well as with the protein processing in ER pathway. High single expression or co-expression of P4HB and GRP78 indicated a shorter OS. When stratified by postoperative adjuvant chemotherapy, high co-expression was only represented for unfavorable prognosis in the group with chemotherapy, especially in advanced stage. Multivariate Cox regression analysis identified differentiation (P = 0.020, HR = 1.846, 95% CI: 1.099-3.101), TNM stage (P < 0.001, HR = 3.124, 95% CI: 1.870-5.217), postoperative adjuvant chemotherapy (P = 0.005, HR = 0.507, 95% CI: 0.317-0.810) and P4HB and GRP78 co-expression (P = 0.002, HR = 2.304, 95% CI: 1.355-3.915) were independent prognostic factors for OS. The nomogram was better than TNM stage in discrimination ability and clinical usefulness from the receiver operating characteristic (ROC) and decision curve analysis (DCA) curves.Conclusion: P4HB may positive correlate with GRP78 expression in GC. Co-expression of them can be an independent prognostic factor, serving as a predictive biomarker for GC patients, especially for advanced stage with postoperative adjuvant chemotherapy. And the nomogram may be better than TNM stage in discrimination ability and clinical usefulness.