Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Department of Immunology, Nantong University School of Medicine, Nantong 226001, China.
Cell Rep. 2018 Nov 20;25(8):2223-2233.e6. doi: 10.1016/j.celrep.2018.10.100.
Pathways underlying metabolic reprogramming in cancer remain incompletely understood. We identify the transmembrane serine protease TMPRSS11B as a gene that promotes transformation of immortalized human bronchial epithelial cells (HBECs). TMPRSS11B is upregulated in human lung squamous cell carcinomas (LSCCs), and high expression is associated with poor survival of non-small cell lung cancer patients. TMPRSS11B inhibition in human LSCCs reduces transformation and tumor growth. Given that TMPRSS11B harbors an extracellular (EC) protease domain, we hypothesized that catalysis of a membrane-bound substrate modulates tumor progression. Interrogation of a set of soluble receptors revealed that TMPRSS11B promotes solubilization of Basigin, an obligate chaperone of the lactate monocarboxylate transporter MCT4. Basigin release mediated by TMPRSS11B enhances lactate export and glycolytic metabolism, thereby promoting tumorigenesis. These findings establish an oncogenic role for TMPRSS11B and provide support for the development of therapies that target this enzyme at the surface of cancer cells.
癌症代谢重编程的潜在机制仍不完全清楚。我们发现跨膜丝氨酸蛋白酶 TMPRSS11B 可促进永生化人支气管上皮细胞（HBEC）的转化。TMPRSS11B 在人肺鳞癌（LSCC）中上调，高表达与非小细胞肺癌患者的不良预后相关。在人 LSCC 中抑制 TMPRSS11B 可减少转化和肿瘤生长。鉴于 TMPRSS11B 含有细胞外（EC）蛋白酶结构域，我们假设催化膜结合底物可调节肿瘤进展。一组可溶性受体的分析表明，TMPRSS11B 促进了乳酸单羧酸转运蛋白 MCT4 的必需伴侣 Basigin 的溶解。TMPRSS11B 介导的 Basigin 释放增强了乳酸的输出和糖酵解代谢，从而促进了肿瘤发生。这些发现确立了 TMPRSS11B 的致癌作用，并为开发针对癌细胞表面这种酶的治疗方法提供了支持。
