Clinically significant association of elevated expression of nuclear factor E2-related factor 2 expression with higher glucose uptake and progression of upper urinary tract cancer.

There is growing evidence that the transcription factor nuclear factor E2-related factor 2 (Nrf2) is the major participant in regulating antioxidants and pathways for detoxifying reactive oxygen species (ROS), as well as having a vital role in tumor proliferation, invasion, and chemoresistance. It was also recently reported that Nrf2 supports cell proliferation by promoting metabolic activity. Thus, Nrf2 is involved in progression of cancer. Upper urinary tract urothelial carcinoma (UTUC) is a biologically aggressive tumor with high rates of recurrence and progression, resulting in a poor prognosis. However, the role of Nrf2 in UTUC is largely unknown. In order to study the role of Nrf2 in UTUC from the metabolic perspective, we retrospectively assessed Nrf2 expression in the surgical specimen and the preoperative maximum standard glucose uptake (SUVmax) on [18F]fluorodeoxy-glucose positron emission tomography (18F-FDG-PET) of 107 patients with UTUC who underwent radical nephroureterectomy. Increased expression of Nrf2 in the primary lesion was correlated with less differentiated histology, local invasion, and lymph node metastasis, and was also an independent indicator of shorter overall survival according to multivariate analysis. Furthermore, increased expression of Nrf2 was associated with higher preoperative SUVmax by the primary tumor on 18F-FDG-PET, while Nrf2 expression and SUVmax were also significantly correlated in the metastatic lymph nodes. Among the 18 patients with lymph node metastasis at nephroureterectomy who underwent retroperitoneal lymph node dissection and received adjuvant chemotherapy, the patients with higher Nrf2 expression in the primary tumor had worse recurrence-free survival. These results suggest that constitutive activation of Nrf2 might be linked with tumor aerobic glycolysis and progression of UTUC, indicating that Nrf2 signaling in the tumor microenvironment promotes progression of UTUC. The online version of this article (10.1186/s12885-018-4427-1) contains supplementary material, which is available to authorized users.

越来越多的证据表明，转录因子核因子E2相关因子2（Nrf2）是调节抗氧化剂和活性氧（ROS）解毒途径的主要参与者，并且在肿瘤增殖、侵袭和化疗耐药中起着至关重要的作用。最近也有报道称Nrf2通过促进代谢活动来支持细胞增殖。因此，Nrf2参与癌症的进展。上尿路尿路上皮癌（UTUC）是一种具有高复发率和进展率的生物学侵袭性肿瘤，预后较差。然而，Nrf2在上尿路尿路上皮癌中的作用在很大程度上尚不清楚。 为了从代谢角度研究Nrf2在上尿路尿路上皮癌中的作用，我们回顾性评估了107例接受根治性肾输尿管切除术的上尿路尿路上皮癌患者手术标本中Nrf2的表达以及[18F]氟脱氧葡萄糖正电子发射断层扫描（18F - FDG - PET）术前的最大标准摄取值（SUVmax）。 原发灶中Nrf2表达增加与分化较差的组织学类型、局部侵袭和淋巴结转移相关，并且根据多变量分析，也是总生存期较短的独立指标。此外，Nrf2表达增加与18F - FDG - PET上原发肿瘤术前较高的SUVmax相关，而Nrf2表达和SUVmax在转移性淋巴结中也显著相关。在18例接受肾输尿管切除术时发现淋巴结转移并进行了腹膜后淋巴结清扫和辅助化疗的患者中，原发肿瘤中Nrf2表达较高的患者无复发生存期更差。 这些结果表明，Nrf2的组成性激活可能与肿瘤有氧糖酵解和上尿路尿路上皮癌的进展有关，这意味着肿瘤微环境中的Nrf2信号传导促进了上尿路尿路上皮癌的进展。 本文的在线版本（10.1186/s12885 - 2018 - 4427 - 1）包含补充材料，授权用户可获取。