GRP78 as a regulator of liver steatosis and cancer progression mediated by loss of the tumor suppressor PTEN.
GRP78 as a regulator of liver steatosis and cancer progression mediated by loss of the tumor suppressor PTEN.
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葡萄糖调节蛋白78（GRP 78）是一种在人类癌症中广泛升高的分子伴侣，对内质网（ER）蛋白折叠、应激信号传导和PI 3 K/AKT激活至关重要。GRP 78的基因敲除模型揭示GRP 78维持代谢器官的稳态，包括肝脏、胰腺和脂肪组织。肝细胞癌（HCC）和胆管癌（CC）是最常见的肝癌。对于HCC和CC缺乏有效的治疗方法，突出了进一步了解肝脏肿瘤发生机制的必要性。PTEN是一种拮抗PI 3 K/AKT通路的肿瘤抑制因子，在广泛的肿瘤中失活，包括40-50%的人类肝癌。为了阐明GRP 78在肝癌中的作用，我们建立了由白蛋白-Cre-重组酶（cPf/f78 f/f）介导的Pten和Grp 78双等位基因肝脏特异性缺失的小鼠模型。有趣的是，与PTEN相反，GRP 78的缺失是进行性的但不完全的。在3个月时，cPf/f78 f/f肝脏显示肝肿大、脂肪生成基因的激活、脂肪变性加重和肝损伤，这意味着GRP 78保护肝脏免受PTEN无效介导的发病机制。此外，在对肝损伤的响应中，我们观察到cPf/f78 f/f肝脏中胆管和肝祖细胞的增殖和扩增增加。引人注目的是，cPf/f78 f/f肝脏中的胆管细胞保持野生型（WT）GRP 78水平，而邻近区域显示GRP 78减少。信号通路分析显示选择性JNK激活、β-连环蛋白下调、沿着PDGFRα上调，这是6个月时cPf/f78 f/f肝脏特有的。HCC和CC的发展在8-9个月时在cPf/f78 f/f肝脏中加速和明显，与癌症病变中的强烈GRP 78表达一致，并且邻近正常区域中的GRP 78表达恢复到WT水平。相比之下，c78 f/f肝脏即使在14个月时也未显示恶性肿瘤。这些研究表明GRP 78是PTEN丢失介导的肝损伤和癌症进展的新型调节剂。
Glucose-regulated protein 78 (GRP78), a molecular chaperone widely elevated in human cancers, is critical for endoplasmic reticulum (ER) protein folding, stress signaling and PI3K/AKT activation. Genetic knockout models of GRP78 revealed that GRP78 maintains homeostasis of metabolic organs, including liver, pancreas and adipose tissues. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the most common liver cancers. There is a lack of effective therapeutics for HCC and CC, highlighting the need to further understand liver tumorigenic mechanisms. PTEN, a tumor suppressor that antagonizes the PI3K/AKT pathway, is inactivated in a wide range of tumors, including 40–50% of human liver cancers. To elucidate the role of GRP78 in liver cancer, we created a mouse model with biallelic liver-specific deletion of Pten and Grp78 mediated by Albumin-Cre-recombinase (cPf/f78f/f). Interestingly, in contrast to PTEN, deletion of GRP78 was progressive but incomplete. At 3 months, cPf/f78f/f livers showed hepatomegaly, activation of lipogenic genes, exacerbated steatosis and liver injury, implying that GRP78 protects the liver against PTEN-null mediated pathogenesis. Furthermore, in response to liver injury, we observed increased proliferation and expansion of bile duct and liver progenitor cells in cPf/f78f/f livers. Strikingly, bile duct cells in cPf/f78f/f livers maintained wild-type (WT) GRP78 level while adjacent areas showed GRP78 reduction. Analysis of signaling pathways revealed selective JNK activation, β-catenin downregulation, along with PDGFRα upregulation, which was unique to cPf/f78f/f livers at 6 months. Development of both HCC and CC was accelerated and evident in cPf/f78f/f livers at 8–9 months, coinciding with intense GRP78 expression in the cancer lesions, and GRP78 expression in adjacent normal areas reverted back to the WT level. In contrast, c78f/f livers showed no malignancy even at 14 months. These studies reveal GRP78 is a novel regulator for PTEN-loss mediated liver injury and cancer progression.