Thrombin cleavage of osteopontin initiates osteopontin's tumor-promoting activity.
Thrombin cleavage of osteopontin initiates osteopontin's tumor-promoting activity.
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DOI：
10.1111/jth.15663
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发表时间：
2022-05
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影响因子：
--
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中科院分区：
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骨桥蛋白 (OPN) 是一种多功能促炎基质细胞蛋白，在多种人类癌症中过度表达，并与肿瘤进展和转移相关。 OPN 的凝血酶裂解揭示了 α4β1 和 α9β1 整联蛋白的隐秘结合位点。生成抗凝血酶裂解 OPNR153A 敲入 (OPN-KI) 小鼠，并将其与 OPN 缺陷小鼠 (OPN-KO) 和野生型 (WT) 小鼠支持黑色素瘤细胞生长的能力进行比较。流式细胞术用于分析肿瘤浸润白细胞。与 WT 小鼠相比，用抗凝血酶裂解 OPN 改造的 OPN-KI 小鼠可以减少 B16 黑色素瘤的生长，减少肺转移。 OPN-KI 小鼠的肿瘤抑制表型与 OPN-KO 小鼠中观察到的相同，并且通过达比加群对凝血酶的药理学抑制在 WT 小鼠中复制。从 OPN-KI 小鼠中分离出的肿瘤具有增加的肿瘤相关巨噬细胞，且激活表型发生了改变。免疫缺陷 OPN-KI 小鼠 (NOG-OPN-KI) 或巨噬细胞耗尽的 OPN-KI 小鼠未表现出肿瘤抑制表型。由于 B16 细胞不表达 OPN，宿主 OPN 的凝血酶裂解片段通过功能性调节肿瘤相关巨噬细胞来抑制宿主抗肿瘤免疫反应。表达 OPN 的 YUMM3.1 细胞在 OPN-KI 和 OPN-KO 小鼠中表现出比 B16 细胞更少的肿瘤抑制作用，但与 B16 细胞类似，达比加群抑制其生长。来自宿主和肿瘤的 OPN 的凝血酶裂解启动 OPN 在体内的促肿瘤活性。
Osteopontin (OPN) is a multifunctional proinflammatory matricellular protein overexpressed in multiple human cancers and associated with tumor progression and metastases. Thrombin cleavage of OPN reveals a cryptic binding site for α4β1 and α9β1 integrins. Thrombin cleavage-resistant OPNR153A knock-in (OPN-KI) mice were generated and compared to OPN deficient mice (OPN-KO) and wild type (WT) mice in their ability to support growth of melanoma cells. Flow cytometry was used to analyze tumor infiltrating leukocytes. OPN-KI mice engineered with a thrombin cleavage-resistant OPN had reduced B16 melanoma growth and fewer pulmonary metastases than WT mice. The tumor suppression phenotype of the OPN-KI mouse was identical to that observed in OPN-KO mice and was replicated in WT mice by pharmacologic inhibition of thrombin with dabigatran. Tumors isolated from OPN-KI mice had increased tumor-associated macrophages with an altered activation phenotype. Immunodeficient OPN-KI mice (NOG-OPN-KI) or macrophage-depleted OPN-KI mice did not exhibit the tumor suppression phenotype. As B16 cells do not express OPN, thrombin-cleaved fragments of host OPN suppress host antitumor immune response by functionally modulating the tumor-associated macrophages. YUMM3.1 cells, which express OPN, showed less tumor suppression in the OPN-KI and OPN-KO mice than B16 cells, but its growth was suppressed by dabigatran similar to B16 cells. Thrombin cleavage of OPN, derived from the host and the tumor, initiates OPN’s tumor-promoting activity in vivo.
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影响因子：
3.7
作者：
Jablonski KA;Amici SA;Webb LM;Ruiz-Rosado Jde D;Popovich PG;Partida-Sanchez S;Guerau-de-Arellano M
通讯作者：
Guerau-de-Arellano M
影响因子：
5.1
作者：
Glass O;Henao R;Patel K;Guy CD;Gruss HJ;Syn WK;Moylan CA;Streilein R;Hall R;Mae Diehl A;Abdelmalek MF
通讯作者：
Abdelmalek MF
影响因子：
4.3
作者：
Meeth K;Wang JX;Micevic G;Damsky W;Bosenberg MW
通讯作者：
Bosenberg MW
影响因子：
5.4
作者：
Herum, Kate M.;Romaine, Andreas;Christensen, Geir
通讯作者：
Christensen, Geir
影响因子：
10.4
作者：
Chai-Adisaksopha, C.;Hillis, C.;Crowther, M.
通讯作者：
Crowther, M.