CRTAC1 在尿路上皮癌中的下调促进肿瘤侵袭性并预示不良预后。

Downregulation of CRTAC1 in Urothelial Carcinoma Promotes Tumor Aggressiveness and Confers Poor Prognosis.

机构信息

Department of Urology, Kaohsiung Medical University Hospital, 807 Kaohsiung, Taiwan.

Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, 807 Kaohsiung, Taiwan.

出版信息

Front Biosci (Landmark Ed). 2023 Sep 24;28(9):217. doi: 10.31083/j.fbl2809217.

DOI:10.31083/j.fbl2809217

PMID:37796703

Abstract

BACKGROUND

Cartilage acidic protein 1 (CRTAC1) is a glycosylated calcium-binding extracellular matrix protein. The oncological functions of CRTAC1 in urothelial carcinoma (UC) of the urinary bladder (UB) and upper urinary tract (UT) have not yet been elucidated. Based on the published UBUC transcriptome data, we re-evaluated the differential expression profile of calcium ion binding-related genes (GO:0005509), and we found that was the most significantly downregulated gene in UBUC progression. Therefore, we analyzed the prognostic value and biological significance of CRTAC1 expression in UC.

METHODS

We used immunohistochemistry to determine the CRTAC1 expression levels in 340 patients with UTUC and 295 patients with UBUC. The CRTAC1 expression was compared with the clinicopathological characteristics, and the prognostic impact of CRTAC1 on metastasis-free survival (MFS) and disease-specific survival (DSS) was evaluated. To study the biological functions of CRTAC1, the proliferation, migration, invasion, and tube formation abilities of UC-derived cells were evaluated.

RESULTS

A low CRTAC1 expression significantly correlated with high tumor stage, high histological grade, perineural invasion, vascular invasion, nodal metastasis, and high mitotic rate (all < 0.01). Moreover, the CRTAC1 immunoexpression status was an independent prognostic factor for MFS and DSS in UBUC and UTUC patients (all < 0.001) in the multivariate analysis. The exogenous expression of CRTAC1 suppressed the cell proliferation, invasion, and angiogenesis, and downregulated the matrix metallopeptidase 2 (MMP2) level in BFTC909 and T24 cells.

CONCLUSIONS

CRTAC1 may participate in progression of UC and serve as a prognostic marker for metastasis. Low CRTAC1 expression was significantly associated with aggressive UC characteristics and worse clinical outcomes. The inclusion of CRTAC1 immunoexpression in the standard pathological variables may optimize the risk stratification of patients.

摘要

背景

软骨酸性蛋白 1（CRTAC1）是一种糖基化的钙结合细胞外基质蛋白。CRTAC1 在膀胱癌（UB）和上尿路尿路上皮癌（UT）中的肿瘤功能尚未阐明。基于已发表的 UBUC 转录组数据，我们重新评估了钙结合相关基因（GO：0005509）的差异表达谱，发现 CRTAC1 是 UBUC 进展过程中下调最显著的基因。因此，我们分析了 CRTAC1 在 UC 中的表达对预后的影响及其生物学意义。

方法

我们使用免疫组织化学法检测了 340 例 UTUC 和 295 例 UBUC 患者的 CRTAC1 表达水平。将 CRTAC1 的表达与临床病理特征进行比较，并评估 CRTAC1 对无转移生存（MFS）和疾病特异性生存（DSS）的预后影响。为了研究 CRTAC1 的生物学功能，评估了 UC 衍生细胞的增殖、迁移、侵袭和管形成能力。

结果

低 CRTAC1 表达与肿瘤分期高、组织学分级高、神经周围侵犯、血管侵犯、淋巴结转移和高有丝分裂率显著相关（均 < 0.01）。此外，在多变量分析中，CRTAC1 免疫表达状态是 UBUC 和 UTUC 患者 MFS 和 DSS 的独立预后因素（均 < 0.001）。CRTAC1 的外源性表达抑制了 BFTC909 和 T24 细胞的增殖、侵袭和血管生成，并下调了基质金属蛋白酶 2（MMP2）水平。