Department of Urology, The Third Medical Center, Chinese PLA General Hospital/Medical School of Chinese PLA/State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing 100853, P.R. China.
Department of Urology, The Third Affiliated Central Hospital of Nankai University, Tianjin 300071, P.R. China.
Int J Oncol. 2022 Jul;61(1). doi: 10.3892/ijo.2022.5377. Epub 2022 Jun 1.
Cell division cycle‑associated 5 (CDCA5) protein, which is involved in cohesion, contributes to cell cycle regulation and chromosome segregation by maintaining genomic stability. Accumulating evidence indicates that CDCA5 expression is upregulated in a number of types of cancer associated with a poor prognosis. However, the biological function of CDCA5 in clear cell renal cell carcinoma (ccRCC) remains largely unknown. In the present study, The Cancer Genome Atlas data mining revealed that CDCA5 was more highly expressed in ccRCC than in adjacent normal tissues. Importantly, such a high expression was associated with a higher risk of distant metastasis and poorer clinical outcomes. Moreover, the clinical and prognostic value of CDCA5 expression was further investigated using immunohistochemistry on tissue microarrays containing paired tumor tissues and adjacent normal tissues from 137 patients with ccRCC. Functional analyses revealed that CDCA5 knockdown significantly inhibited the proliferation and migration of ccRCC cells, and suppressed the growth of xenografts in nude mice. Mechanistically, CDCA5 knockdown induced severe DNA damage with the persistent accumulation of γ‑H2A histone family member X foci, resulting in G2/M cell cycle arrest and finally, in chromosomal instability and apoptosis. CDCA5 knockdown significantly decreased the phosphorylation levels of Stat3 and NF‑κB, suggesting that CDCA5 plays a role in regulating the inflammatory response. Collectively, the findings of the present study indicate that ccRCC cells require CDCA5 for malignant progression, and that CDCA5 inhibition may enhance the outcomes of patients with high‑risk ccRCC.
细胞分裂周期相关蛋白 5（CDCA5）参与黏附作用，通过维持基因组稳定性来促进细胞周期调控和染色体分离。越来越多的证据表明，CDCA5 在与预后不良相关的多种类型癌症中表达上调。然而，CDCA5 在透明细胞肾细胞癌（ccRCC）中的生物学功能在很大程度上尚不清楚。在本研究中，通过对癌症基因组图谱数据进行挖掘发现，与相邻正常组织相比，CDCA5 在 ccRCC 中表达更高。重要的是，这种高表达与远处转移风险增加和临床结局较差相关。此外，还通过对包含 137 例 ccRCC 患者肿瘤组织和相邻正常组织的组织微阵列进行免疫组织化学分析，进一步研究了 CDCA5 表达的临床和预后价值。功能分析表明，CDCA5 敲低显著抑制 ccRCC 细胞的增殖和迁移，并抑制裸鼠异种移植瘤的生长。机制上，CDCA5 敲低诱导严重的 DNA 损伤，导致 γ-H2A 组蛋白家族成员 X 焦点持续积累，从而导致 G2/M 细胞周期阻滞，最终导致染色体不稳定和细胞凋亡。CDCA5 敲低显著降低了 Stat3 和 NF-κB 的磷酸化水平，表明 CDCA5 在调节炎症反应中发挥作用。总之，本研究的结果表明，ccRCC 细胞需要 CDCA5 来促进恶性进展，而 CDCA5 抑制可能会增强高危 ccRCC 患者的治疗效果。
