Overexpression of GRP78 and GRP94 are markers for aggressive behavior and poor prognosis in gastric carcinomas

Zheng, Haixue; Takahashi, Hiroyuki; Li, Xiaohan; Hara, Takuya; Masuda, Shinji; Guan, Yifu; Takano, Yasuo

doi:10.1016/j.humpath.2007.11.009

Cited by 167 publications

(120 citation statements)

References 28 publications

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“…This finding is contradictory to several reports in the literature showing increased GRP94 expression in a variety of malignant tumors or cancer cell lines, such as breast (23), oral (24), lung (25), gastric (26), esophageal (27) and colonic carcinomas (28). Using immunohistochemistry we observed that GRP94 was absent or weakly present in ductal cells but strongly present in acinar cells in chronic pancreatitis and normal pancreatic tissues.…”

Section: Discussioncontrasting

confidence: 99%

Silencing of GRP94 expression promotes apoptosis in pancreatic cancer cells

Zheng

Erkan²,

Streit³

et al. 2009

Int J Oncol

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Abstract. As a molecular chaperone, GRP94 is the most abundant glycoprotein in the endoplasmic reticulum, playing an important role in maintaining cellular homeostasis. Here, we investigated the expression and the role of GRP94 in regulating cell growth and apoptosis in pancreatic cancer cells. GRP94 mRNA levels were analyzed by QRT-PCR. Immunohistochemistry was performed to localize GRP94 in tissues of the normal pancreas (n=20), chronic pancreatitis (n=20) and pancreatic ductal adenocarcinoma (n=44). Silencing of GRP94 expression was carried out by transfection with specific siRNA oligonucleotides. Apoptosis was induced by treatment with actinomycin D. Compared to normal pancreatic tissues, median mRNA levels of GRP94 were 1.5-and 3.7-fold (p<0.05) lower in chronic pancreatitis and pancreatic cancer tissues, respectively. GRP94 protein was strongly expressed in normal acinar cells and moderately expressed in normal ductal cells. GRP94 expression was lost in 48% of the cancer cases. Moderate or strong staining in cancer cells was observed in 32 and 20% of pancreatic cancer tissues, respectively. Silencing GRP94 by siRNA increased apoptosis of pancreatic cancer cells in vitro. Patients with higher than the median expression have a tendency for a worsened survival. When the small number of patients with the highest expression (n=3) were compared with the rest of the group (n=41), the survival difference was significantly worse (5 vs. 18 months, respectively, p=0.006). Downregulation of GRP94 decreases apoptosis resistance in pancreatic cancer cells. Clinically, patients with high GRP94 expression show a tendency for a worsened survival.

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Section: Discussioncontrasting

confidence: 99%

Silencing of GRP94 expression promotes apoptosis in pancreatic cancer cells

Zheng

Erkan²,

Streit³

et al. 2009

Int J Oncol

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“…13,14 We observed that activation of the UPR was significantly associated with H. pylori-positive GC (12/13, 92%). Increased expression of HSPA5 in the IM of H. pylori-positive subjects with and without GC rules out field cancerization and suggests induction of the UPR occurs early in the evolution of the metaplasia to dysplasia.…”

Section: Discussionmentioning

confidence: 89%

“…10,12 In GC patients, activation of the UPR, as evidenced by the upregulation of HSPA5 has been observed in up to 47% of gastric carcinoma and is associated with increased metastasis and poor prognosis. 13,14 As IM and SPEM cause expansion of secretory lineage cells and aberrant expression of trefoil factors and acidic mucins, we hypothesized that this increase in protein synthesis within this precancerous MM might also induce ER stress and contribute to carcinogenesis. In this study, we demonstrate that the UPR is activated non-cell autonomously in Helicobacter-induced metaplasia and dysplasia in both the human and mouse models of GC, highlighting a significant role of the UPR in mediating the progression of metaplasia to dysplasia under chronic Helicobacter infection.…”

mentioning

confidence: 99%

The unfolded protein response is activated in Helicobacter-induced gastric carcinogenesis in a non-cell autonomous manner

Baird

Ang

Clark

et al. 2013

Laboratory Investigation

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Mucous metaplasia (MM) is an aberrant secretory phenotype that arises during Helicobacter-induced gastric carcinogenesis. HSPA5, a key modulator of the unfolded protein response (UPR) activated by endoplasmic reticulum (ER) stress is overexpressed in gastric cancer (GC). We studied activation of the UPR in MM and GC in humans and mice. We assessed RNA and protein levels of ER stress markers (HSPA5, XBP1, and CHOP) in human GC, and correlated with Helicobacter pylori (H. pylori) status, then surveyed HSPA5 in normal gastric mucosa and gastric pre-neoplasia including gastritis and intestinal metaplasia (IM). The role of H. pylori infection in the UPR was assessed by co-culture with AGS GC cells. ER stress markers in metaplasia and dysplasia from transgenic K19-Wnt1/C2mE mice and C57Bl/6 mice with chronic Helicobacter felis (H. felis) infection were compared. HSPA5 was overexpressed in 24/73 (33%) of human GC. Induction of HSPA5 and XBP1 splicing was associated with H. pylori-associated GC (P ¼ 0.007 for XBP1 splicing). HSPA5 was overexpressed in MM but not gastritis in patients with H. pylori infection. Stimulation of AGS cells with CagA-positive H. pylori suppressed HSPA5 expression and XBP1 splicing. In the normal gastric mucosa of human and mouse, HSPA5 was constitutively expressed in MIST1-positive chief cells. Increased Hspa5 and Chop expression were found in dysplasia of C57Bl/6 mice with chronic H. felis infection but was absent in spontaneous gastric dysplasia in K19-Wnt1/C2mE mice with concomitant loss of Mist1 expression, similar to that observed in H. pylori-associated human GC. Induction of the UPR in the milieu of Helicobacter-induced chronic inflammation and MM may promote neoplastic transformation of Helicobacter-infected gastric mucosa. KEYWORDS: endoplasmic reticulum stress; germfree; mucous metaplasia; unfolded protein response Helicobacter pylori (H. pylori) is a major risk factor for human gastric cancer (GC). 1 Sustained interaction between H. pylori and the gastric epithelium induces chronic inflammation and loss of parietal cells (oxyntic atrophy), leading to development of mucous metaplasia (MM)-intestinal metaplasia (IM) and spasmolytic polypeptide expressing metaplasia (SPEM). 2 Studies in human and murine models indicate that IM and SPEM are critical neoplastic precursors in the cascade of gastric carcinogenesis. [3][4][5][6] IM is characterized by the presence of intestinal goblet cells with simultaneous expressions of TFF3 and MUC2 7 while SPEM, named for its characteristic expression of spasmolytic polypeptide (TFF2), expresses MUC6 and resembles deep antral gland cells. 5 Reported studies suggest that SPEM, derived from transdifferentiation of chief cells, 8 gives rise to IM and ultimately dysplasia in the setting of oxyntic atrophy and chronic inflammation. 9 Despite characterization of the sequence and origin of metaplastic mucous cell lineage, the mechanisms responsible for neoplastic transformation of the secretory cell lineage are not understood.Cancer cells are under constant e...

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“…Intracellular proteotoxic stress and UPR is a common accompaniment of cancer cell transformation (12)(13)(14). Consistent with this, elevated levels of protective GRP78 have been shown to have an important role in the pathogenesis of several types of cancers, in which it confers poor prognosis (15,16). Conversely, homozygous deletion of GRP78 in prostate epithelium inhibits prostate tumorigenesis (17).…”

Section: Introductionmentioning

confidence: 79%

Treatment with Panobinostat Induces Glucose-Regulated Protein 78 Acetylation and Endoplasmic Reticulum Stress in Breast Cancer Cells

Rao

Nalluri

Kolhe

et al. 2010

Molecular Cancer Therapeutics

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Increased levels of misfolded polypeptides in the endoplasmic reticulum (ER) triggers the dissociation of glucose-regulated protein 78 (GRP78) from the three transmembrane ER-stress mediators, i.e., protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF6), and inositol-requiring enzyme 1α, which results in the adaptive unfolded protein response (UPR). In the present studies, we determined that histone deacetylase-6 (HDAC6) binds and deacetylates GRP78. Following treatment with the pan-histone deacetylase inhibitor panobinostat (Novartis Pharmaceuticals), or knockdown of HDAC6 by short hairpin RNA, GRP78 is acetylated in 11 lysine residues, which dissociates GRP78 from PERK. This is associated with the activation of a lethal UPR in human breast cancer cells. Coimmunoprecipitation studies showed that binding of HDAC6 to GRP78 requires the second catalytic and COOH-terminal BUZ domains of HDAC6. Treatment with panobinostat increased the levels of phosphorylated-eukaryotic translation initiation factor (p-eIF2α), ATF4, and CAAT/enhancer binding protein homologous protein (CHOP). Panobinostat treatment also increased the proapoptotic BIK, BIM, BAX, and BAK levels, as well as increased the activity of caspase-7. Knockdown of GRP78 sensitized MCF-7 cells to bortezomib and panobinostat-induced UPR and cell death. These findings indicate that enforced acetylation and decreased binding of GRP78 to PERK is mechanistically linked to panobinostat-induced UPR and cell death of breast cancer cells. Mol Cancer Ther; 9(4); 942-52. ©2010 AACR.

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Overexpression of GRP78 and GRP94 are markers for aggressive behavior and poor prognosis in gastric carcinomas

Cited by 167 publications

References 28 publications

Silencing of GRP94 expression promotes apoptosis in pancreatic cancer cells

Silencing of GRP94 expression promotes apoptosis in pancreatic cancer cells

The unfolded protein response is activated in Helicobacter-induced gastric carcinogenesis in a non-cell autonomous manner

Treatment with Panobinostat Induces Glucose-Regulated Protein 78 Acetylation and Endoplasmic Reticulum Stress in Breast Cancer Cells

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