title: B7-H3 silencing increases paclitaxel sensitivity by abrogating Jak2/Stat3 phosphorylation.
abstract: In many types of cancer, the expression of the immunoregulatory protein B7-H3 has been associated with poor prognosis. Previously, we observed a link between B7-H3 and tumor cell migration and invasion, and in present study, we have investigated the role of B7-H3 in chemoresistance in breast cancer. We observed that silencing of B7-H3, via stable short hairpin RNA or transient short interfering RNA transfection, increased the sensitivity of multiple human breast cancer cell lines to paclitaxel as a result of enhanced drug-induced apoptosis. Overexpression of B7-H3 made the cancer cells more resistant to the drug. Next, we investigated the mechanisms behind B7-H3-mediated paclitaxel resistance and found that the level of Stat3 Tyr705 phosphorylation was decreased in B7-H3 knockdown cells along with the expression of its direct downstream targets Mcl-1 and survivin. The phosphorylation of Janus kinase 2 (Jak2), an upstream molecule of Stat3, was also significantly decreased. In contrast, reexpression of B7-H3 in B7-H3 knockdown and low B7-H3 expressing cells increased the phosphorylation of Jak2 and Stat3. In vivo animal experiments showed that B7-H3 knockdown tumors displayed a slower growth rate than the control xenografts. Importantly, paclitaxel treatment showed a strong antitumor activity in the mice with B7-H3 knockdown tumors, but only a marginal effect in the control group. Taken together, our data show that in breast cancer cells, B7-H3 induces paclitaxel resistance, at least partially by interfering with Jak2/Stat3 pathway. These results provide novel insight into the function of B7-H3 and encourage the design and testing of approaches targeting this protein and its partners.
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Christina
authors.initials: C
authors.lastname: Tekle
authors.forename: Yih-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Alexandr
authors.initials: A
authors.lastname: Kristian
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.forename: Zixing
authors.initials: Z
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Gunhild Mari
authors.initials: GM
authors.lastname: Mælandsmo
authors.forename: Jahn Marthin
authors.initials: JM
authors.lastname: Nesland
authors.forename: Oystein
authors.initials: O
authors.lastname: Fodstad
authors.forename: Ming
authors.initials: M
authors.lastname: Tan
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D060887:B7 Antigens; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D053614:Janus Kinase 2 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000077022:Survivin
chemical_list: D015703:Antigens, CD; D000972:Antineoplastic Agents, Phytogenic; D060887:B7 Antigens; C107489:BIRC5 protein, human; C423237:CD276 protein, human; D051034:Inhibitor of Apoptosis Proteins; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077022:Survivin; D053614:Janus Kinase 2; D017239:Paclitaxel