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: zihai@musc.edu

This article has been accepted for publication and undergone full peer review but has not beethrough the copyediting, typesetting, pagination and proofreading process which may lead todifferences between this version and the Version of Record. Please cite this article asdoi: 10.1002/hep.27400

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-

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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.

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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.

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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;26:215-

226.

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.

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