Zou Hai-Ying, Lv Guo-Qing, Dai Li-Hua, Zhan Xiu-Hui, Jiao Ji-Wei, Liao Lian-Di, Zhou Tai-Mei, Li Chun-Quan, Wu Bing-Li, Xu Li-Yan, Li En-Min
Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Medical College of Shantou University, Shantou 515041, PR China; Department of Biochemistry and Molecular Biology, Medical College of Shantou University, Shantou 515041, PR China.
Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Medical College of Shantou University, Shantou 515041, PR China; Institute of Oncologic Pathology, Medical College of Shantou University, Shantou 515041, PR China.
Int J Biochem Cell Biol. 2016 Jun;75:85-98. doi: 10.1016/j.biocel.2016.04.003. Epub 2016 Apr 8.
Lysyl oxidase-like 2 (LOXL2) is a member of the lysyl oxidase family, which plays an important role in extracellular matrix protein biosynthesis and tumor progression. In the present study, we identified a novel splice variant, LOXL2Δ72, which encodes a peptide having the same N- and C-termini as wild-type LOXL2 (LOXL2WT), but lacks 72 nucleotides encoding 24 amino acids. LOXL2Δ72 had dramatically reduced enzymatic activity, and was no longer secreted. However, LOXL2Δ72 promoted greater cell migration and invasion than LOXL2WT. Furthermore, a dual luciferase reporter assay indicated that LOXL2Δ72 activates distinct signal transduction pathways compared to LOXL2WT, consistent with cDNA microarray data showing different expression levels of cell migration- and invasion-related genes induced following over-expression of each LOXL2 isoform. In particular, LOXL2Δ72 distinctly promoted esophageal squamous cell carcinoma (ESCC) cell migration via up-regulating the C-C motif chemokine ligand 28 (CCL28). Our results suggest that the new LOXL2 splice variant contributes to tumor progression by novel molecular mechanisms different from LOXL2WT.
赖氨酰氧化酶样2（LOXL2）是赖氨酰氧化酶家族的一员，在细胞外基质蛋白生物合成和肿瘤进展中起重要作用。在本研究中，我们鉴定出一种新的剪接变体LOXL2Δ72，它编码的肽与野生型LOXL2（LOXL2WT）具有相同的N端和C端，但缺少编码24个氨基酸的72个核苷酸。LOXL2Δ72的酶活性显著降低，且不再分泌。然而，与LOXL2WT相比，LOXL2Δ72促进了更强的细胞迁移和侵袭。此外，双荧光素酶报告基因检测表明，与LOXL2WT相比，LOXL2Δ72激活了不同的信号转导途径，这与cDNA微阵列数据一致，该数据显示每种LOXL2异构体过表达后诱导的细胞迁移和侵袭相关基因的表达水平不同。特别是，LOXL2Δ72通过上调C-C基序趋化因子配体28（CCL28）明显促进食管鳞状细胞癌（ESCC）细胞迁移。我们的结果表明，新的LOXL2剪接变体通过不同于LOXL2WT的新分子机制促进肿瘤进展。
