Kuo Wei-Ting, Lee Yi-Chen, Yang Yi-Fang, Cheng Ching-Feng, Tseng Ching-Jiunn, Tsai Kuo-Wang
Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taiwan.
J Cancer. 2024 Aug 13;15(16):5318-5328. doi: 10.7150/jca.97537. eCollection 2024.
Bladder cancer is the most prevalent type of cancer in Taiwan, and therefore, enhancing the diagnostic sensitivity of biomarkers for early-stage tumors and identifying therapeutic targets to improve patient survival rates are essential. Although Sushi Domain Containing 2 (SUSD2) dysfunction has been identified in several types of human cancer, its biological role in bladder cancer remains unclear. Analysis of The Cancer Genome Atlas revealed significantly higher expression of SUSD2 mRNA in bladder cancer tissues than in adjacent normal tissues. This elevated expression of SUSD2 significantly correlated with pathological stage ( = 0.029), pN stage ( < 0.001), and pM stage ( = 0.047). Univariate analysis revealed that high SUSD2 expression was associated with decreased overall survival (crude hazard ratio = 1.70, 95% confidence interval = 1.13-2.56, = 0.01). Multivariate analysis revealed a significant correlation between high SUSD2 expression and poor survival outcomes (adjusted hazard ratio = 1.53, 95% confidence interval = 1.01-2.31, = 0.043). IHC analysis revealed a significant correlation between elevated SUSD2 protein levels and unfavorable pathological stages ( < 0.001). SUSD2 suppression significantly reduced the proliferation, colony formation, and invasion of bladder cancer cells. In addition, cell cycle analysis revealed that SUSD2 knockdown induced G2/M phase arrestin bladder cancer cells. Tumor Immune Estimation Resource analysis indicated that expression of SUSD2 was significantly associated with macrophage infiltration and M2 macrophage polarization in bladder cancer. In addition, miR-383-5p directly targeted the 3'UTR of SUSD2, with its ectopic expression inhibiting the growth and motility of bladder cancer cells. Our study revealed that miR-383-5p/SUSD2 axis dysfunction may contribute to a poor prognosis for bladder cancer by affecting cell growth, metastasis, and the tumor microenvironment.
膀胱癌是台湾地区最常见的癌症类型，因此，提高生物标志物对早期肿瘤的诊断敏感性并确定治疗靶点以提高患者生存率至关重要。尽管在几种人类癌症中已发现含寿司结构域蛋白2（SUSD2）功能异常，但其在膀胱癌中的生物学作用仍不清楚。癌症基因组图谱分析显示，膀胱癌组织中SUSD2 mRNA的表达明显高于相邻正常组织。SUSD2的这种高表达与病理分期（P = 0.029）、pN分期（P < 0.001）和pM分期（P = 0.047）显著相关。单因素分析显示，SUSD2高表达与总生存期降低相关（粗风险比 = 1.70，95%置信区间 = 1.13 - 2.56，P = 0.01）。多因素分析显示，SUSD2高表达与不良生存结果显著相关（调整后风险比 = 1.53，95%置信区间 = 1.01 - 2.31，P = 0.043）。免疫组化分析显示，SUSD2蛋白水平升高与不良病理分期显著相关（P < 0.001）。SUSD2抑制显著降低了膀胱癌细胞的增殖、集落形成和侵袭。此外，细胞周期分析显示，SUSD2敲低诱导膀胱癌细胞G2/M期阻滞。肿瘤免疫估计资源分析表明，SUSD2的表达与膀胱癌中的巨噬细胞浸润和M2巨噬细胞极化显著相关。此外，miR - 383 - 5p直接靶向SUSD2的3'UTR，其异位表达抑制膀胱癌细胞的生长和运动。我们的研究表明，miR - 383 - 5p/SUSD2轴功能异常可能通过影响细胞生长、转移和肿瘤微环境导致膀胱癌预后不良。
