Giatromanolaki Alexandra, Sivridis Efthimios, Kalamida Dimitra, Koukourakis Michael I
Department of Pathology, Democritus University of Thrace Medical School, University General Hospital of Alexandroupolis, Alexandroupolis, Greece.
Department of Radiotherapy-Oncology, Democritus University of Thrace Medical School, University General Hospital of Alexandroupolis, Alexandroupolis, Greece.
Clin Breast Cancer. 2017 Jun;17(3):e119-e125. doi: 10.1016/j.clbc.2016.11.006. Epub 2016 Nov 23.
Disrupting the autophagic balance to trigger autophagic death may open new strategies for cancer therapy. Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and may play a role in cancer biology and clinical behavior.
The expression of TFEB and the lysosomal cancer cell content (expression of lysosomal associated membrane protein 2a [LAMP2a] and cathepsin D) was studied in a series of 100 T1-stage breast carcinomas. Expression patterns were correlated with autophagy/hypoxia-related proteins, angiogenesis, and clinical outcome. The effect of hypoxic/acidic conditions on TFEB kinetics was studied in the MCF-7 cancer cell line.
Overexpression of TFEB in cancer cell cytoplasm and the perinuclear/nuclear area was noted in 23 (23%) of 100 cases. High LAMP2a and cathepsin D expression was noted in 30 (30%) of 100 and 28 (28%) of 100 cases, respectively. TFEB expression was directly linked with LAMP2a (P < .0001, r = 0.53), cathepsin D (P = .0002, r = 0.36), light chain 3A (LC3A) (P = .02, r = 0.22), and hypoxia-inducible factor 2-alpha (HIF-2α) (P = .01, r = 0.25) expression and inversely with progesterone receptor (P = .01, r = 0.22). High vascular density was directly linked with LAMP2a (P = .05, r = 0.18) and cathepsin D (P = .005, r = 0.28). In Kaplan-Meier survival analysis, TFEB and cathepsin D expression were related to an ominous prognosis (P = .001 and P = .03, respectively). In multivariate analysis, TFEB expression sustained its independent prognostic significance (P = .05, hazard ratio 2.1). In in vitro experiments, acidity triggered overexpression of TFEB and nuclear translocation.
Intense TFEB expression and lysosomal biogenesis, evident in one fourth of early breast carcinomas, define poor prognosis. Tumor acidity is among the microenvironmental conditions that trigger TFEB overactivity. TFEB is a sound target for the development of lysosomal targeting therapies.
破坏自噬平衡以触发自噬性死亡可能为癌症治疗开辟新策略。转录因子EB（TFEB）是溶酶体生物发生的主要调节因子，可能在癌症生物学和临床行为中发挥作用。
在100例T1期乳腺癌中研究了TFEB的表达以及溶酶体细胞含量（溶酶体相关膜蛋白2a [LAMP2a]和组织蛋白酶D的表达）。表达模式与自噬/缺氧相关蛋白、血管生成和临床结果相关。在MCF-7癌细胞系中研究了缺氧/酸性条件对TFEB动力学的影响。
100例中有23例（23%）出现癌细胞胞质及核周/核区域TFEB过表达。100例中有30例（30%）和28例（28%）分别出现高LAMP2a和组织蛋白酶D表达。TFEB表达与LAMP2a（P <.0001，r = 0.53）、组织蛋白酶D（P =.0002，r = 0.36）、轻链3A（LC3A）（P =.02，r = 0.22）和缺氧诱导因子2α（HIF-2α）（P =.01，r = 0.25）表达直接相关，与孕激素受体呈负相关（P =.01，r = 0.22）。高血管密度与LAMP2a（P =.05，r = 0.18）和组织蛋白酶D（P =.005，r = 0.28）直接相关。在Kaplan-Meier生存分析中，TFEB和组织蛋白酶D表达与不良预后相关（分别为P =.001和P =.03）。在多变量分析中，TFEB表达保持其独立的预后意义（P =.05，风险比2.1）。在体外实验中，酸性触发TFEB过表达和核转位。
在四分之一的早期乳腺癌中明显存在的强烈TFEB表达和溶酶体生物发生预示着不良预后。肿瘤酸性是触发TFEB过度活性的微环境条件之一。TFEB是溶酶体靶向治疗开发的一个合理靶点。
