Uemoto Yasuaki, Katsuta Eriko, Kondo Naoto, Wanifuchi-Endo Yumi, Fujita Takashi, Asano Tomoko, Hisada Tomoka, Terada Mitsuo, Kato Akiko, Okuda Katsuhiro, Sugiura Hiroshi, Komura Masayuki, Kato Hiroyuki, Osaga Satoshi, Takahashi Satoru, Toyama Tatsuya
Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences Nagoya, Aichi, Japan.
Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center Buffalo, NY, USA.
Am J Cancer Res. 2022 Apr 15;12(4):1593-1605. eCollection 2022.
HECT domain E3 ubiquitin ligase 1 (HECTD1) has been reported to be a negative regulator of epithelial-mesenchymal transition and to decrease breast cancer invasion and metastasis. However, the clinical significance and detailed role of HECTD1 in breast cancer remain elusive. We investigated the role of HECTD1 in two large breast cancer cohorts at our institution and The Cancer Genome Atlas using mRNA expression and bioinformatics analysis. We also examined the prognostic significance of HECTD1 mRNA expression by multivariate analysis and HECTD1 protein expression by immunohistochemistry using our cohort. HECTD1 mRNA expression was significantly lower in breast cancer tissues compared with those in adjacent normal tissues (P<0.001). HECTD1 mRNA expression levels also differed among breast cancer subtypes. Decreased HECTD1 mRNA expression was significantly associated with aggressive tumor characteristics, including large tumor size and high histological grade. HECTD1 mRNA expression was inversely associated with mitochondrial cellular respiratory function (oxidative phosphorylation (P<0.001, FDR -value <0.001) the respiratory chain complex (P<0.001, FDR -value <0.001) and reactive oxygen species (P<0.001, FDR -value <0.001), but not with epithelial-mesenchymal transition, in breast cancer tissues. Low expression of HECTD1 mRNA was associated with shorter disease-free survival (log-rank: P=0.013) and overall survival (log-rank: P=0.038) in breast cancer patients. Multivariate analysis also identified low HECTD1 mRNA expression level as an independent risk factor for disease-free (hazard ratio: 1.54, 95% confidence interval: 1.11-2.13, P=0.009) and overall (hazard ratio: 1.50, 95% confidence interval: 1.01-2.24, P=0.046) survival among breast cancer patients. There was no association of HECTD1 protein expression with HECTD1 mRNA expression and prognosis. In conclusion, we identified low expression of HECTD1 mRNA as an independent poor prognostic factor in breast cancer and showed that HECTD1 mRNA expression was inversely correlated with genes involved in mitochondrial cellular respiratory function in breast cancer.
据报道，HECT结构域E3泛素连接酶1（HECTD1）是上皮-间质转化的负调节因子，可减少乳腺癌的侵袭和转移。然而，HECTD1在乳腺癌中的临床意义和具体作用仍不清楚。我们利用mRNA表达和生物信息学分析，在我们机构的两个大型乳腺癌队列以及癌症基因组图谱中研究了HECTD1的作用。我们还通过多变量分析研究了HECTD1 mRNA表达的预后意义，并使用我们的队列通过免疫组织化学检测了HECTD1蛋白表达。与相邻正常组织相比，乳腺癌组织中HECTD1 mRNA表达显著降低（P<0.001）。HECTD1 mRNA表达水平在乳腺癌亚型之间也存在差异。HECTD1 mRNA表达降低与侵袭性肿瘤特征显著相关，包括肿瘤体积大、组织学分级高。在乳腺癌组织中，HECTD1 mRNA表达与线粒体细胞呼吸功能（氧化磷酸化，P<0.001，FDR值<0.001）、呼吸链复合物（P<0.001，FDR值<0.001）和活性氧（P<0.001，FDR值<0.001）呈负相关，但与上皮-间质转化无关。HECTD1 mRNA低表达与乳腺癌患者较短的无病生存期（对数秩检验：P=0.013）和总生存期（对数秩检验：P=0.038）相关。多变量分析还确定HECTD1 mRNA低表达水平是乳腺癌患者无病（风险比：1.54，95%置信区间：1.11-2.13，P=0.009）和总（风险比：1.50，95%置信区间：1.01-2.24，P=0.046）生存期的独立危险因素。HECTD1蛋白表达与HECTD1 mRNA表达及预后无关。总之，我们确定HECTD1 mRNA低表达是乳腺癌独立的不良预后因素，并表明HECTD1 mRNA表达与乳腺癌中线粒体细胞呼吸功能相关基因呈负相关。
