Pathology Department, Faculty of Medicine, Menoufia University, Shibin El Kom, Menoufia, 32511, Egypt.
Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Menoufia University, Shibin El Kom, Menoufia, Egypt.
Diagn Pathol. 2023 Nov 23;18(1):125. doi: 10.1186/s13000-023-01409-6.
Globally Renal Cell Carcinoma (RCC) represents 3% of malignant tumours in adults and 1.78% in Egypt. AMPK-related protein kinase 5 (ARK5) is mainly associated with a hypoxic microenvironment which is a feature of the major RCC subtypes. Additionally, it displays decreased mitochondrial respiration. SIRT3 is a mitochondrial deacetylase that modifies multiple mitochondrial proteins.
Fifty eight cases of RCC, and 30 non-neoplastic cases (of End-Stage Kidney Disease (ESKD) were subjected to immunohistochemistry by ARK5 and SIRT3. The results of IHC were correlated together and correlated with the available clinicopathologic and survival data.
Although no significant difference was detected between RCC and ESKD groups regarding ARK5 expression, there was a significant association with RCC regarding H-score and nucleocytoplasmic expression (both P = 0.001). Also, SIRT3 was highly expressed in RCC in comparison to the ESKD group (H-score: P = 0.001). There were significant associations between nucleocytoplasmic ARK5 expression and higher tumour grade, low apoptotic and high mitotic indices, tumour extent, advanced tumour stage, and impaired response of tumours to chemotherapeutic drugs (P = 0.039, P = 0.001, P = 0.027, P = 0.011, P = 0.009, and P = 0.014 respectively). Moreover, the H score of ARK5 expression showed significant associations with tumour grade, apoptotic and mitotic indices, tumour extension, tumour stage, and response to therapy (P = 0.01, 0.035, 0.001, 0.004. 0.003 and 0.013). Regarding SIRT3 expression, it showed significant associations with apoptotic and mitotic indices, tumour extent, tumour stage and response to therapy (P = 0.022, 0.02, 0.042, 0.039 and 0.027). Interestingly, there was a highly significant correlation between the expression of ARK5 and SIRT3 (P = 0.009). Univariate survival analysis revealed a significant association between short survival duration and both nucleocytoplasmic expression of ARK5 and positive SIRT3 expression (P = 0.014 and 0.035).
ARK5 and SIRT3 are overexpressed in RCC and associated with parameters of poor prognosis as well as short survival. Both seem to influence response to therapy in RCC. So, they could be new targets for therapy that may improve tumour response and patients' survival. There is a postulated relationship that needs more extensive investigation.
全球范围内，肾细胞癌（RCC）在成年人中的恶性肿瘤占比为 3%，在埃及占比为 1.78%。AMP 相关蛋白激酶 5（ARK5）主要与缺氧微环境相关，缺氧微环境是 RCC 主要亚型的特征之一。此外，它还显示出线粒体呼吸减少。SIRT3 是一种线粒体去乙酰化酶，可修饰多种线粒体蛋白。
对 58 例 RCC 和 30 例非肿瘤性病例（终末期肾病（ESKD）进行免疫组织化学检测 ARK5 和 SIRT3。将 IHC 的结果进行相关性分析，并与现有的临床病理和生存数据进行相关性分析。
虽然 ARK5 表达在 RCC 和 ESKD 组之间没有显著差异，但在 RCC 中与 H 评分和核浆表达有显著相关性（均 P = 0.001）。此外，与 ESKD 组相比，SIRT3 在 RCC 中高表达（H 评分：P = 0.001）。核浆 ARK5 表达与肿瘤分级较高、凋亡和有丝分裂指数较低、肿瘤范围较大、肿瘤分期较晚以及肿瘤对化疗药物反应较差之间存在显著相关性（P = 0.039、P = 0.001、P = 0.027、P = 0.011、P = 0.009 和 P = 0.014）。此外，ARK5 表达的 H 评分与肿瘤分级、凋亡和有丝分裂指数、肿瘤范围、肿瘤分期和治疗反应均有显著相关性（P = 0.01、0.035、0.001、0.004、0.003 和 0.013）。关于 SIRT3 表达，它与凋亡和有丝分裂指数、肿瘤范围、肿瘤分期和治疗反应呈显著相关性（P = 0.022、0.02、0.042、0.039 和 0.027）。有趣的是，ARK5 和 SIRT3 的表达之间存在高度显著的相关性（P = 0.009）。单因素生存分析显示，核浆 ARK5 表达和 SIRT3 阳性表达与较短的生存时间之间存在显著相关性（P = 0.014 和 0.035）。
ARK5 和 SIRT3 在 RCC 中过度表达，并与预后不良参数以及较短的生存期相关。两者似乎都影响 RCC 对治疗的反应。因此，它们可能成为改善肿瘤反应和患者生存的新治疗靶点。两者之间存在假定的关系，需要更广泛的研究。
