Correspondence to Hepatology (2014)
Endoplasmic reticulum heat shock protein gp96/grp94 is a pro-oncogenic chaperone not a tumor suppressor
Saleh Rachidi1, Shaoli Sun2 and Zihai Li1*
Department of Microbiology and Immunology1, Pathology and Laboratory Medicine2, Medical University of South Carolina, Charleston, SC
*Corresponding author. Email: [email protected]
This article has been accepted for publication and undergone full peer review but has not bee through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.27400
Hepatology
Page 2 of 5
To the Editor:
We read with great interest the article by Chen et al. published in Hepatology (1). gp96, or grp94, is an endoplasmic reticulum (ER) HSP90 that chaperones many strategically important clienteles in oncogenesis including integrin, Toll-like receptor, Wnt co-receptor and insulin-like growth factor. However, Chen et al. demonstrated that conditional deletion of hsp90b1 (encoding gp96) and Pten from mouse livers using Cre recombinase driven by Albumin promoter (Alb-Cre) increased liver tumorigenesis (1). Nevertheless, the gp96 status of these tumors was not reported, leaving open a possibility of gp96 being either a tumor suppressor (if tumors were gp96-) or a pro-oncogenic chaperone (if gp96+). This diametrically opposing viewpoint is important to clarify particularly because liver-specific knockout of pro-tumorigenic genes could result in paradoxical enhancement of tumorigenesis from cells that escaped cre-mediated deletion (2). Herein, by crossing the same Alb-cre mice with our independently generated hsp90b1flox/flox mice (3, 4), we also probed the roles of gp96 in liver oncogenesis. We found that knockout (KO) mice were more susceptible to hepatocyte carcinogenesis than wild type (WT) mice in response to diethyl-nitrosoamine (DENA), but the developing tumors were exclusively gp96+, due to an age-dependent expansion of the residual WT hepatocytes (Figure 1).
The development of gp96+ but not gp96- tumors in the same hosts illustrated its tumor-promoting rather than tumor-suppressive role. It might be prudent to examine if the Pten-loss tumors in the study of Chen et al. were also gp96+, analogous to another study on ER chaperone grp78 (5). It was found that liver cancer develops from escaping residual grp78+ hepatocytes after intended biallelic liver-
Hepatology
Page 3 of 5
Hepatology
specific deletion of Pten and grp78 via Albumin-Cre. The shared but apparently non-redundant cellular function of grp78 and gp96 in liver cancer underscores the critical oncogenic roles of both chaperones.
Hepatology
Hepatology
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Figure 1. Alb-cre-gp96flox/flox mice (KO) have increased liver carcinogenesis from residual gp96+ hepatocytes. (A) Representative images of WT and KO tumors. (B) Quantification of liver tumors from WT and KO mice 62 weeks post DENA injection.
Hepatology
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Hepatology
References: 1. Chen WT, Tseng CC, Pfaffenbach K, Kanel G, Luo B, Stiles BL, Lee AS. Liver-specific knockout of GRP94 in mice disrupts cell adhesion, activates liver progenitor cells, and accelerates liver tumorigenesis. Hepatology 2014;59:947-957. 2. Sekine S, Ogawa R, Kanai Y. Hepatomas with activating Ctnnb1 mutations in 'Ctnnb1-deficient' livers: a tricky aspect of a conditional knockout mouse model. Carcinogenesis 2011;32:622-628. 3. Yang Y, Liu B, Dai J, Srivastava PK, Zammit DJ, Lefrancois L, Li Z. Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages. Immunity 2007;26:215226. 4. Staron M, Yang Y, Liu B, Li J, Shen Y, Zuniga-Pflucker JC, Aguila HL, et al. gp96, an endoplasmic reticulum master chaperone for integrins and Toll-like receptors, selectively regulates early T and B lymphopoiesis. Blood 2010;115:2380-2390. 5. Chen WT, Zhu G, Pfaffenbach K, Kanel G, Stiles B, Lee AS. GRP78 as a regulator of liver steatosis and cancer progression mediated by loss of the tumor suppressor PTEN. Oncogene 2013.
Hepatology
Endoplasmic reticulum heat shock protein gp96/grp94 is a pro-oncogenic chaperone not a tumor suppressor
Saleh Rachidi1, Shaoli Sun2 and Zihai Li1*
Department of Microbiology and Immunology1, Pathology and Laboratory Medicine2, Medical University of South Carolina, Charleston, SC
*Corresponding author. Email: [email protected]
This article has been accepted for publication and undergone full peer review but has not bee through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.27400
Hepatology
Page 2 of 5
To the Editor:
We read with great interest the article by Chen et al. published in Hepatology (1). gp96, or grp94, is an endoplasmic reticulum (ER) HSP90 that chaperones many strategically important clienteles in oncogenesis including integrin, Toll-like receptor, Wnt co-receptor and insulin-like growth factor. However, Chen et al. demonstrated that conditional deletion of hsp90b1 (encoding gp96) and Pten from mouse livers using Cre recombinase driven by Albumin promoter (Alb-Cre) increased liver tumorigenesis (1). Nevertheless, the gp96 status of these tumors was not reported, leaving open a possibility of gp96 being either a tumor suppressor (if tumors were gp96-) or a pro-oncogenic chaperone (if gp96+). This diametrically opposing viewpoint is important to clarify particularly because liver-specific knockout of pro-tumorigenic genes could result in paradoxical enhancement of tumorigenesis from cells that escaped cre-mediated deletion (2). Herein, by crossing the same Alb-cre mice with our independently generated hsp90b1flox/flox mice (3, 4), we also probed the roles of gp96 in liver oncogenesis. We found that knockout (KO) mice were more susceptible to hepatocyte carcinogenesis than wild type (WT) mice in response to diethyl-nitrosoamine (DENA), but the developing tumors were exclusively gp96+, due to an age-dependent expansion of the residual WT hepatocytes (Figure 1).
The development of gp96+ but not gp96- tumors in the same hosts illustrated its tumor-promoting rather than tumor-suppressive role. It might be prudent to examine if the Pten-loss tumors in the study of Chen et al. were also gp96+, analogous to another study on ER chaperone grp78 (5). It was found that liver cancer develops from escaping residual grp78+ hepatocytes after intended biallelic liver-
Hepatology
Page 3 of 5
Hepatology
specific deletion of Pten and grp78 via Albumin-Cre. The shared but apparently non-redundant cellular function of grp78 and gp96 in liver cancer underscores the critical oncogenic roles of both chaperones.
Hepatology
Hepatology
Page 4 of 5
Figure 1. Alb-cre-gp96flox/flox mice (KO) have increased liver carcinogenesis from residual gp96+ hepatocytes. (A) Representative images of WT and KO tumors. (B) Quantification of liver tumors from WT and KO mice 62 weeks post DENA injection.
Hepatology
Page 5 of 5
Hepatology
References: 1. Chen WT, Tseng CC, Pfaffenbach K, Kanel G, Luo B, Stiles BL, Lee AS. Liver-specific knockout of GRP94 in mice disrupts cell adhesion, activates liver progenitor cells, and accelerates liver tumorigenesis. Hepatology 2014;59:947-957. 2. Sekine S, Ogawa R, Kanai Y. Hepatomas with activating Ctnnb1 mutations in 'Ctnnb1-deficient' livers: a tricky aspect of a conditional knockout mouse model. Carcinogenesis 2011;32:622-628. 3. Yang Y, Liu B, Dai J, Srivastava PK, Zammit DJ, Lefrancois L, Li Z. Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages. Immunity 2007;26:215226. 4. Staron M, Yang Y, Liu B, Li J, Shen Y, Zuniga-Pflucker JC, Aguila HL, et al. gp96, an endoplasmic reticulum master chaperone for integrins and Toll-like receptors, selectively regulates early T and B lymphopoiesis. Blood 2010;115:2380-2390. 5. Chen WT, Zhu G, Pfaffenbach K, Kanel G, Stiles B, Lee AS. GRP78 as a regulator of liver steatosis and cancer progression mediated by loss of the tumor suppressor PTEN. Oncogene 2013.
Hepatology
