title: 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.
authors.affiliation: Department of Cell Biology, Cell Engineering Research Centre, State Key Laboratory of Cancer Biology, State Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: J
authors.initials: J
authors.lastname: Tang
authors.forename: Y-S
authors.initials: YS
authors.lastname: Guo
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: X-L
authors.initials: XL
authors.lastname: Yu
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: W
authors.initials: W
authors.lastname: Huang
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: B
authors.initials: B
authors.lastname: Chen
authors.forename: J-L
authors.initials: JL
authors.lastname: Jiang
authors.forename: Z-N
authors.initials: ZN
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051926:Basigin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D019473:Transcription Factors, TFII / Q000378:metabolism; D014158:Transcription, Genetic; D056811:Unfolded Protein Response; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; C104259:GTF2I protein, human; D006360:Heat-Shock Proteins; D034741:RNA, Small Interfering; D019473:Transcription Factors, TFII; D051926:Basigin; D004317:Doxorubicin; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases