Derlin-1 is overexpressed in human breast carcinoma and protects cancer cells from endoplasmic reticulum stress-induced apoptosis

Wang, Jiao; Hua, Hui; Ran, Yuliang; Zhang, Hongyin; Liu, Weiping; Yang, Zhihua; Jiang, Yangfu

doi:10.1186/bcr1849

Cited by 50 publications

(73 citation statements)

References 32 publications

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“…Derlin-1 was up-regulated by these treatments as well as GPR78 ( Supplementary Fig. S5), which is concordant with the result of Wang et al (9). Membrane location of Derlin-1 was frequently observed in the cancerous tissues but was seldom observed in nonmalignant tissues (Fig.…”

Section: Resultssupporting

confidence: 80%

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Derlin-1 Is Overexpressed on the Tumor Cell Surface and Enables Antibody-Mediated Tumor Targeting Therapy

Ran

Hu²,

Hu³

et al. 2008

Clinical Cancer Research

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Purpose: Tumor targeting therapy is one of the most promising strategies for anticancer treatment. Derlin-1has been reported to participate in misfolded protein dislocation and integrates into the endoplasmic reticulum (ER) membrane to survey for such protein aggregates. We elucidate herein that Derlin-1can leak to the plasmalemma from the ER in tumor cells and may have clinical application as a novel cancer target in the hope of developing a new tumor targeting therapy. Experimental Design: The cell surface expression of Derlin-1 was shown by immunofluorescence analysis of nonpermeabilized cells andWestern blotting of fractional proteins of tumor cells. Derlin-1expression in cancerous tissues was also shown by immunohistochemistry. Biodistribution analysis and g-scintigraphic imaging were done using 125 I-labeled Derlin-1targeting antibody in isogenic mice models. Finally, tumor-bearing mice were treated by the anti-Derlin-1polyclonal antibody and monoclonal antibodies. Results: Derlin-1 was expressed on various tumor cell surfaces and adopted a homodimer conformation. Robust cytoplasmic and membrane expression of Derlin-1was detected in various types of human cancers tissues but was not correlated with any clinicopathologic features of pancreatic cancer. Derlin-1 directed antibodies specifically targeted to colon tumors and significantly suppress tumor growth in isogenic mice. Conclusions: These preclinical data show that Derlin-1 protein is a functional molecular target expressed on the tumor cell surface and is a candidate therapeutic target that may be translated into clinical applications.

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Section: Resultssupporting

confidence: 80%

“…Derlin-1 expression is up-regulated by inducers of ER stress in yeast (8) and Caenorhabditis elegans (6) and suppresses ER stress-induced apoptosis in tumor cells (9). Almost all solid tumors encounter ER stress, such as hypoxia, and tumor growth depends on an intact unfolded protein response (10 -13).…”

mentioning

confidence: 99%

Derlin-1 Is Overexpressed on the Tumor Cell Surface and Enables Antibody-Mediated Tumor Targeting Therapy

Ran

Hu²,

Hu³

et al. 2008

Clinical Cancer Research

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“…NFB has a known role in PEL tumorigenesis. It is modulated by the KSHV homolog of the cellular FLICE inhibitory protein (vFLIP) 52,58 as well as KSHV K15. 59 Of note, the EBV latency membrane protein 1 (LMP-1) can also activate NFB.…”

Section: Discussionmentioning

confidence: 99%

“…DERL1 and ETV1 have previously been associated with viral and nonviral cancers. 51,52 DERL1 protects cells from endoplasmic reticulum (ER) stress-induced apoptosis and is overexpressed in breast cancer. 52 Multiple reports have shown associations between solid tumors and ETV1, and alteration in ETV1 is a prognostic marker in tumor progression.…”

Section: Discussionmentioning

confidence: 99%

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Tumor suppressor genes FHIT and WWOX are deleted in primary effusion lymphoma (PEL) cell lines

Roy

Sin

Damania

et al. 2011

Blood

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Derlin‐1 exhibits oncogenic activities and indicates an unfavorable prognosis in breast cancer

Qing

Zeng

Cai

et al. 2019

Cell Biology International

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Derlin‐1 is involved in the elimination of misfolded proteins and has been implicated in the progression of human cancers. However, its prognostic value and biological function in breast cancer remain unknown. Here, we show that Derlin‐1 is overexpressed in breast cancer and exhibits oncogenic activities via interaction with UBE2C. Increased expression of Derlin‐1 is correlated with lymph node metastasis, advanced clinical stage, and unfavorable overall survival in two cohorts containing over 1,000 patients. Multivariate analyses by the Cox regression model suggest Derlin‐1 is an independent factor for poor prognosis. In vitro experiments demonstrate that Derlin‐1 expression is transcriptionally upregulated by c‐Myc. Ectopic expression of Derlin‐1 promotes breast cancer cell proliferation and migration, whereas the knockdown of Derlin‐1 results in the opposite phenotypes. Mechanistically, Derlin‐1 directly binds to UBE2C to increase the phosphorylation of AKT and ERK. The treatment of UBE2C siRNA markedly attenuates Derlin‐1‐mediated cell growth and migration. Collectively, our data suggest Derlin‐1 is a potential prognostic factor and functions as an oncogene in breast cancer.

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Derlin-1 is overexpressed in human breast carcinoma and protects cancer cells from endoplasmic reticulum stress-induced apoptosis

Cited by 50 publications

References 32 publications

Derlin-1 Is Overexpressed on the Tumor Cell Surface and Enables Antibody-Mediated Tumor Targeting Therapy

Derlin-1 Is Overexpressed on the Tumor Cell Surface and Enables Antibody-Mediated Tumor Targeting Therapy

Tumor suppressor genes FHIT and WWOX are deleted in primary effusion lymphoma (PEL) cell lines

Derlin‐1 exhibits oncogenic activities and indicates an unfavorable prognosis in breast cancer

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