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CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma.

ABSTRACT: The unfolded protein response (UPR) is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. However, tumor-specific UPR transducers are largely unknown. In the present study, we identified CD147, a cancer biomarker, as an UPR inducer in hepatocellular carcinoma (HCC). The expression of the major UPR target, Bip, was found to be positively associated with CD147 in human hepatoma tissues. By phosphorylating FAK and Src, CD147-enhanced TFII-I tyrosine phosphorylation at Tyr248. CD147 also induced p-TFII-I nuclear localization and binding to the Bip promoter where endoplasmic reticulum (ER) stress response element 1 (ERSE1) (-82/-50) is the most efficient target of the three ERSEs, thus increasing transcription of Bip. Furthermore, by inducing UPR, CD147 inhibited HCC cell apoptosis and decreased cell Adriamycin chemosensitivity, thus decreasing the survival rate of hepatoma-bearing nude mice. Together, these results reveal pivotal roles for CD147 in modulating the UPR in HCC and raise the possibility that CD147 is a target that promotes HCC cell apoptosis and increases the sensitivity of tumors to anti-cancer drugs. Therefore, CD147 inhibition provides an opportunity to enhance the efficacy of existing agents and represents a novel target for HCC treatment.

SUBMITTER: Tang J

PROVIDER: S-EPMC3469060 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma.

Tang J J Guo Y-S YS Zhang Y Y Yu X-L XL Li L L Huang W W Li Y Y Chen B B Jiang J-L JL Chen Z-N ZN

Cell death and differentiation 20120518 11

The unfolded protein response (UPR) is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. However, tumor-specific UPR transducers are largely unknown. In the present study, we identified CD147, a cancer biomarker, as an UPR inducer in hepatocellular carcinoma (HCC). The expression of the major UPR target, Bip, was found to be positively associated with CD147 in human hepatoma tissues. By phosphorylating FAK and Src, CD147-enhanced TFII-I tyrosine ph ...[more]

PMID: 22595757

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Project description:Hepatocytes are epithelial cells with highly specialized polarity. The disorder and loss of hepatocyte polarity leads to a weakness of cell adhesion and connection, the induction of epithelial-mesenchymal transition, and eventually the occurrence of hepatocellular carcinoma (HCC). Cluster of differentiation 147 (CD147), a tumor-related glycoprotein, promotes epithelial-mesenchymal transition and the invasion of HCC. However, the function of CD147 in hepatocyte depolarization is unknown. Here we identified that CD147 was basolaterally polarized in hepatocyte membrane of liver tissues and HepG2 cells. CD147 not only promoted transforming growth factor-?1-mediated hepatocyte polarity loss but also directly induced endocytosis and down-regulation of E-cadherin which contributed to hepatocyte depolarization. Overexpression of CD147 induced Src activation and subsequently recruited ubiquitin ligase Hakai for E-cadherin ubiquitination and lysosomal degradation, leading to decreases of partitioning defective 3 expression and ?-catenin nuclear translocation. This signal transduction was initiated by competitive binding of CD147 with integrin ?1 that interrupted the interaction between the Arg-Gly-Asp motif of fibronectin and integrin ?1. The specific antibodies targeting integrin ?5 and ?1 reversed the decrease of E-cadherin and partitioning defective 3 levels induced by CD147 overexpression. In human liver tissues, CD147 polarity rates significantly declined from liver cirrhosis (71.4%) to HCC (10.4%). CD147-polarized localization negatively correlated with Child-Pugh scores in human liver cirrhosis (r = -0.6092, P < 0.0001) and positively correlated with differentiation grades in HCC (r = 0.2060, P = 0.004). HCC patients with CD147-polarized localization had significantly better overall survival than patients with CD147 nonpolarity (P = 0.021). CONCLUSION:The ectopic CD147-polarized distribution on basolateral membrane promotes hepatocyte depolarization by activation of the CD147-integrin ?5?1-E-cadherin ubiquitination-partitioning defective 3 decrease and ?-catenin translocation signaling cascade, replenishing a molecular pathway in hepatic carcinogenesis. (Hepatology 2018;68:317-332).

Dataset Information

CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma.

Publications

CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma.

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