Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Department of Immunology, Nara Medical University, Kashihara, Japan.
PLoS One. 2021 Nov 24;16(11):e0254289. doi: 10.1371/journal.pone.0254289. eCollection 2021.
Aberrant activation of the Ras/Raf/ERK (extracellular-signal-regulated kinase)-MAPK (mitogen-activated protein kinase) pathway is involved in the progression of cancer, including urothelial carcinoma; but the negative regulation remains unclear. In the present study, we investigated pathological expression of Spred2 (Sprouty-related EVH1 domain-containing protein 2), a negative regulator of the Ras/Raf/ERK-MAPK pathway, and the relation to ERK activation and Ki67 index in various categories of 275 urothelial tumors obtained from clinical patients. In situ hybridization demonstrated that Spred2 mRNA was highly expressed in high-grade non-invasive papillary urothelial carcinoma (HGPUC), and the expression was decreased in carcinoma in situ (CIS) and infiltrating urothelial carcinoma (IUC). Immunohistochemically, membranous Spred2 expression, important to interact with Ras/Raf, was preferentially found in HGPUC. Interestingly, membranous Spred2 expression was decreased in CIS and IUC relative to HGPUC, while ERK activation and the expression of the cell proliferation marker Ki67 index were increased. HGPUC with membranous Spred2 expression correlated significantly with lower levels of ERK activation and Ki67 index as compared to those with negative Spred2 expression. Thus, our pathological findings suggest that Spred2 counters cancer progression in non-invasive papillary carcinoma possibly through inhibiting the Ras/Raf/ERK-MAPK pathway, but this regulatory mechanism is lost in cancers with high malignancy. Spred2 appears to be a key regulator in the progression of non-invasive bladder carcinoma.
Ras/Raf/ERK（细胞外信号调节激酶）-MAPK（丝裂原活化蛋白激酶）通路的异常激活与包括尿路上皮癌在内的癌症进展有关；但负调控仍不清楚。在本研究中，我们研究了 Spred2（Sprouty 相关 EVH1 结构域蛋白 2）的病理表达，Spred2 是 Ras/Raf/ERK-MAPK 通路的负调节剂，以及与 ERK 激活和 Ki67 指数在临床患者获得的 275 例尿路上皮肿瘤的各种类别之间的关系。原位杂交表明，Spred2mRNA 在高级别非浸润性乳头状尿路上皮癌（HGPUC）中高度表达，在原位癌（CIS）和浸润性尿路上皮癌（IUC）中表达降低。免疫组织化学显示，与 Ras/Raf 相互作用的重要膜 Spred2 表达优先存在于 HGPUC 中。有趣的是，与 HGPUC 相比，CIS 和 IUC 中的膜 Spred2 表达减少，而 ERK 激活和细胞增殖标志物 Ki67 指数的表达增加。与阴性 Spred2 表达相比，具有膜 Spred2 表达的 HGPUC 与较低水平的 ERK 激活和 Ki67 指数显着相关。因此，我们的病理学发现表明，Spred2 通过抑制 Ras/Raf/ERK-MAPK 通路可能在非浸润性乳头状癌中对抗癌症进展，但这种调节机制在恶性程度较高的癌症中丧失。Spred2 似乎是非浸润性膀胱癌进展的关键调节剂。
