KLK8 promotes the proliferation and metastasis of colorectal cancer via the activation of EMT associated with PAR1.
KLK8 promotes the proliferation and metastasis of colorectal cancer via the activation of EMT associated with PAR1.
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KLK8通过激活与PAR1相关的EMT促进结直肠癌的增殖和转移
DOI：
10.1038/s41419-021-04149-x
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发表时间：
2021-09-22
影响因子：
9
通讯作者：
Xu P
中科院分区：
文献类型：
--
作者：
Hua Q;Sun Z;Liu Y;Shen X;Zhao W;Zhu X;Xu P
激肽释放酶相关肽酶8(KLK8)在多种肿瘤中起癌基因或抑癌基因的作用，KLK8的异常表达参与了多种肿瘤的发生发展。然而，KLK8在结直肠癌(CRC)中的作用和潜在机制仍很不清楚。本研究通过CCK-8体外集落形成实验和裸鼠体内移植瘤模型，研究了KLK8的致癌作用。通过体外转移实验和裸鼠体内转移模型观察KLK8对肿瘤转移的促进作用。通过生物信息学分析和机理实验阐明了其分子机制。在此，我们报道了KLK8对RKO和SW480细胞的增殖、迁移和侵袭有促进作用。上皮性−间质转化在KLK8促癌作用中起重要作用。此外，蛋白水解酶激活受体-1(PAR-1)拮抗剂SCH79797而非蛋白水解酶激活受体-2(PAR-2)拮抗剂FSLLRY-NH2可抑制KLK8上调的RKO和SW480细胞的增殖、迁移和侵袭。PAR-1拮抗剂SCH79797能减少移植瘤模型的肿瘤体积，减少转移模型肝内的转移结节。此外，SCH79797在体内外均能逆转KLK8对结直肠癌EMT过程的积极影响。综上所述，这些发现首次证明了KLK8促进了EMT和CRC的进展，这种作用可能至少部分地通过PAR1依赖的途径来介导。
Kallikrein-related peptidase 8 (KLK8) acts as an oncogene or anti-oncogene in various tumours, and the abnormal expression of KLK8 is involved in the carcinogenesis of several tumours. However, the role of KLK8 in colorectal cancer (CRC) and the underlying mechanism remain largely unclear. In this study, the carcinogenic effect of KLK8 was determined via CCK-8 and colony formation assays in vitro and a xenograft model in nude mice in vivo. The metastasis-promoting effect of KLK8 was investigated with transwell migration and invasion assays and wound-healing assay in vitro and a metastasis model in nude mice in vivo. Bioinformatics analyses and mechanistic experiments were conducted to elucidate the molecular mechanism. Herein, we reported that KLK8 had a promotive effect on the proliferation, migration and invasion of RKO and SW480 cells. Epithelial−mesenchymal transition (EMT) played an important role in the promotive effects of KLK8 on CRC. In addition, protease-activated receptor-1 (PAR-1) antagonist SCH79797 but not protease-activated receptor-2 (PAR-2) antagonist FSLLRY-NH2 attenuated the proliferation, migration and invasion of KLK8-upregulated RKO and SW480 cells. PAR-1 antagonist SCH79797 reduced the tumour volume of xenograft model and decreased the metastatic nodules in the livers of metastasis model. Furthermore, SCH79797 could reverse the positive impact of KLK8 on the EMT process in CRC both in vitro and in vivo. Taken together, these findings demonstrated for the first time that KLK8 promoted EMT and CRC progression, and this effect might be, at least partly mediated by PAR1-dependent pathway.
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EMT亚型影响上皮可塑性和细胞迁移模式。
影响因子：
11.8
作者：
Aiello NM;Maddipati R;Norgard RJ;Balli D;Li J;Yuan S;Yamazoe T;Black T;Sahmoud A;Furth EE;Bar-Sagi D;Stanger BZ
通讯作者：
Stanger BZ
影响因子：
4.8
作者：
Eissa, Azza;Amodeo, Vanessa;Diamandis, Eleftherios P.
通讯作者：
Diamandis, Eleftherios P.
影响因子：
6
作者：
Gratio, Valerie;Loriot, Celine;Darmoul, Dalila
通讯作者：
Darmoul, Dalila
影响因子：
6.2
作者：
Kim, Jong-Tae;Song, Eun Young;Lee, Hee Gu
通讯作者：
Lee, Hee Gu
影响因子：
2.8
作者：
Alexopoulou, Dimitra K.;Papadopoulos, Iordanis N.;Scorilas, Andreas
通讯作者：
Scorilas, Andreas