Agr2 Mediates Paracrine Effects on Stromal Fibroblasts That Promote Invasion by Gastric Signet-Ring Carcinoma Cells

Tsuji, Tadahiro; Satoyoshi, Rika; Aiba, Namiko; Kubo, Takanori; Yanagihara, Kazuyoshi; Maeda, Daichi; Goto, Akiteru; Ishikawa, Kazuo; Yashiro, Masakazu; Tanaka, Masamitsu

doi:10.1158/0008-5472.can-14-1693

Cited by 36 publications

(25 citation statements)

References 40 publications

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“…and paracrine effect on the Fibro. to facilitate cell migration which is correlated with recent work published by Tsuji et al [30]. It is also important to note that externally applied AGR2 accelerated early activation of Fibro.…”

Section: Discussionsupporting

confidence: 85%

“…by regulating the formation of focal adhesions. These AGR2 functions in wound healing involve FAK and JNK signaling pathways and require AGR2 adhesion domain (amino acids [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. Our finding indicates that external AGR2 may represent an alternative strategy for the development of therapeutics for wounds with large exposure area or difficult-to-heal chronic wounds.…”

Section: Introductionmentioning

confidence: 97%

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Anterior gradient 2 is induced in cutaneous wound and promotes wound healing through its adhesion domain

et al. 2017

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Anterior gradient 2 (AGR2), a member of protein disulfide isomerase (PDI) family, is both located in cytoplasm and secreted into extracellular matrix. The orthologs of AGR2 have been linked to limb regeneration in newt and wound healing in zebrafish. In mammals, AGR2 influences multiple cell signaling pathways in tumor formation and in normal cell functions related to new tissue formation like angiogenesis. However, the function of AGR2 in mammalian wound healing remains unknown. This study aimed to investigate AGR2 expression and its function during skin wound healing and the possible application of external AGR2 in cutaneous wound to accelerate the healing process. Our results showed that AGR2 expression was induced in the migrating epidermal tongue and hyperplastic epidermis after skin excision. Topical application of recombinant AGR2 significantly accelerated wound-healing process by increasing the migration of keratinocytes (Kera.) and the recruitment of fibroblasts (Fibro.) near the wounded area. External AGR2 also promoted the migration of Kera. and Fibro. in vitro in a dose-dependent manner. The adhesion domain of AGR2 was required for the formation of focal adhesions in migrating Fibro., leading to the directional migration along AGR2 gradient. These results indicate that recombinant AGR2 accelerates skin wound healing through regulation of Kera. and Fibro. migration, thus demonstrating its potential utility as an alternative strategy of the therapeutics to accelerate the healing of acute or chronic skin wounds.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 97%

Anterior gradient 2 is induced in cutaneous wound and promotes wound healing through its adhesion domain

et al. 2017

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“…Cancer-secreted AGR2 could activate stromal fibroblasts (cancer-associated stromal cells vs . normal tissue stromal cells) to promote fibroblast associated cancer invasion of gastric cancer cells [19]. AGR2 could activate ER stress response genes [11], to stimulate cell proliferation of AGR2-negative pancreatic tumor cells, and to enhance drug resistance [10].…”

Section: Introductionmentioning

confidence: 99%

Cancer-secreted AGR2 induces programmed cell death in normal cells

et al. 2016

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Anterior Gradient 2 (AGR2) is a protein expressed in many solid tumor types including prostate, pancreatic, breast and lung. AGR2 functions as a protein disulfide isomerase in the endoplasmic reticulum. However, AGR2 is secreted by cancer cells that overexpress this molecule. Secretion of AGR2 was also found in salamander limb regeneration. Due to its ubiquity, tumor secretion of AGR2 must serve an important role in cancer, yet its molecular function is largely unknown. This study examined the effect of cancer-secreted AGR2 on normal cells. Prostate stromal cells were cultured, and tissue digestion media containing AGR2 prepared from prostate primary cancer 10-076 CP and adenocarcinoma LuCaP 70CR xenograft were added. The control were tissue digestion media containing no AGR2 prepared from benign prostate 10-076 NP and small cell carcinoma LuCaP 145.1 xenograft. In the presence of tumor-secreted AGR2, the stromal cells were found to undergo programmed cell death (PCD) characterized by formation of cellular blebs, cell shrinkage, and DNA fragmentation as seen when the stromal cells were UV irradiated or treated by a pro-apoptotic drug. PCD could be prevented with the addition of the monoclonal AGR2-neutralizing antibody P3A5. DNA microarray analysis of LuCaP 70CR media-treated vs. LuCaP 145.1 media-treated cells showed downregulation of the gene SAT1 as a major change in cells exposed to AGR2. RT-PCR analysis confirmed the array result. SAT1 encodes spermidine/spermine N1-acetyltransferase, which maintains intracellular polyamine levels. Abnormal polyamine metabolism as a result of altered SAT1 activity has an adverse effect on cells through the induction of PCD.

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“…Lucia Sommerova et al described that loss of intracellular AGR2 in cell lines caused a variation from epithelial to mesenchymal phenotype and establishment of intracellular AGR2 expression launched EMT 43 . However, other studies suggested that extracellular AGR2 could interrupt adherens junctions, disrupt basal laminin and activate broblastassociated cancer invasion, promoting epithelial morphogenesis and tumorigenesis 44 . To date, no researches about correlation between AGR2 and ribosome biogenesis have been reported.…”

Section: Dicussionmentioning

confidence: 99%

Integrative analysis of AGR2 based on data mining reveals new insights in breast cancer

Zhou¹,

Zhang²,

Liu³

et al. 2020

Preprint

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Background: Belonging to the protein disulfide isomerase (PDI) family, anterior gradient 2 (AGR2) is overexpressed in mucus-secreting cells and endocrine organs such as breast, lung, and ovarian, but its exact function and regulation remain unclear. We aimed to perform integrative analysis of AGR2 in breast cancer.Methods: In our study, a serious of bioinformatic online databases were used to analyze the expression, regulation, prognostic value, and function of AGR2 in breast cancer.Results: The results suggested that AGR2 mRNA was overexpressed in non-basal-like or non-triple-negative breast cancer, but underexpressed in basal-like/ triple-negative breast cancer. AGR2 mRNA expression was correlated with its protein expression. Moreover, the expression of AGR2 was lower in more malignant breast cancer. Furthermore, we also found that DNA methylation, rather than copy number variation, led to AGR2 mRNA overexpression. Prognosis analysis showed no significant correlation between AGR2 level and survival, but in subtype investigation, patients with higher AGR2 level had a significantly better outcome in patients with basal-like / triple-negative breast cancer. Enrichment analysis for co-expression genes of AGR2 revealed that gene sets enriched for chromosome segregation, DNA conformation change, chromosomal region, and GABA receptor activity may play important roles in breast cancer, and that the most significant pathway was “ribosome biogenesis in eukaryotes”, in which negative co-expression genes of AGR2 were enriched.Conclusions: Overexpression of AGR2 was found in less malignant breast cancer, for the first time, our results propose that DNA methylation rather than copy number variation leads to AGR2 overexpression, which can predict favorable prognosis in basal-like/ triple-negative breast cancer, and AGR2 could be a possible regulator of ribosome biogenesis in patients with breast cancer.

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Agr2 Mediates Paracrine Effects on Stromal Fibroblasts That Promote Invasion by Gastric Signet-Ring Carcinoma Cells

Cited by 36 publications

References 40 publications

Anterior gradient 2 is induced in cutaneous wound and promotes wound healing through its adhesion domain

Anterior gradient 2 is induced in cutaneous wound and promotes wound healing through its adhesion domain

Cancer-secreted AGR2 induces programmed cell death in normal cells

Integrative analysis of AGR2 based on data mining reveals new insights in breast cancer

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