2016年5月，杨林博士课题组在《Cancer Cell》上发表题为“Tight Junction Protein 1 Modulates Proteasome Capacity and Proteasome Inhibitor Sensitivity in Multiple Myeloma via EGFR/JAK1/STAT3 Signaling”的论文，揭示了多发性骨髓瘤产生耐药的一个重要机制。此项研究由杨林博士和MD Anderson Cancer Center 的Robert Z. Orlowski博士合作完成。
Cancer Cell. 2016 May 9;29(5):639-52. doi: 10.1016/j.ccell.2016.03.026. Epub 2016 Apr 28.
题目：
Tight Junction Protein 1 Modulates Proteasome Capacity and Proteasome Inhibitor Sensitivity in Multiple Myeloma via EGFR/JAK1/STAT3 Signaling.
作者：
Zhang XD1, Baladandayuthapani V2, Lin H2, Mulligan G3, Li B3, Esseltine DL3, Qi L4, Xu J5, Hunziker W5, Barlogie B6, Usmani SZ7, Zhang Q7, Crowley J8, Hoering A8, Shah JJ9, Weber DM9, Manasanch EE9, Thomas SK9, Li BZ9, Wang HH9, Zhang J2, Kuiatse I9, Tang JL10, Wang H9, He J9, Yang J9, Milan E11, Cenci S11, Ma WC9, Wang ZQ9, Davis RE9, Yang L12, Orlowski RZ13.
单位：
1Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Cyrus Tang Hematology Center, Soochow University, Suzhou, Jiangsu 215123, China; Xi'an Jiaotong University Suzhou Academy, Suzhou, Jiangsu 215123, China.
2Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
3Millennium: The Takeda Oncology Company, Cambridge, MA 02139, USA.
4Xi'an Jiaotong University Suzhou Academy, Suzhou, Jiangsu 215123, China.
5Institute of Molecular and Cell Biology, Singapore 138673, Republic of Singapore.
6Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
7Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; Department of Hematologic Oncology, Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC 28204, USA.
8Cancer Research and Biostatistics, Seattle, WA 98101, USA.
9Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
10Cyrus Tang Hematology Center, Soochow University, Suzhou, Jiangsu 215123, China.
11Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Università Vita-Salute San Raffaele, Milan 20132, Italy.
12Cyrus Tang Hematology Center, Soochow University, Suzhou, Jiangsu 215123, China; Xi'an Jiaotong University Suzhou Academy, Suzhou, Jiangsu 215123, China. Electronic address: yanglin@suda.edu.cn.
13Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: rorlowsk@mdanderson.org.
摘要：
Proteasome inhibitors have revolutionized outcomes in multiple myeloma, but they are used empirically, and primary and secondary resistance are emerging problems. We have identified TJP1 as a determinant of plasma cell proteasome inhibitor susceptibility. TJP1 suppressed expression of the catalytically active immunoproteasome subunits LMP7 and LMP2, decreased proteasome activity, and enhanced proteasome inhibitor sensitivity in vitro and in vivo. This occurred through TJP1-mediated suppression of EGFR/JAK1/STAT3 signaling, which modulated LMP7 and LMP2 levels. In the clinic, high TJP1 expression in patient myeloma cells was associated with a significantly higher likelihood of responding to bortezomib and a longer response duration, supporting the use of TJP1 as a biomarker to identify patients most likely to benefit from proteasome inhibitors.
