Inhibition of CEMIP potentiates the effect of sorafenib on metastatic hepatocellular carcinoma by reducing the stiffness of lung metastases.
Inhibition of CEMIP potentiates the effect of sorafenib on metastatic hepatocellular carcinoma by reducing the stiffness of lung metastases.
复制标题
抑制 CEMIP 通过降低肺转移瘤的硬度来增强索拉非尼对转移性肝细胞癌的作用
DOI：
10.1038/s41419-023-05550-4
复制
发表时间：
2023-01-13
影响因子：
9
通讯作者：
Zhu, Kangshun
中科院分区：
文献类型：
--
作者：
Liu, Mingyu;Xie, Lulu;Zhang, Yuying;Chen, Jianning;Zhang, Xiang;Chen, Ye;Huang, Wensou;Cai, Mingyue;Liang, Licong;Lai, Miaoling;Huang, Jingjun;Guo, Yongjian;Lin, Liteng;Zhu, Kangshun
肝细胞癌(简称肝细胞癌)合并肺转移预后差，治疗效果差。研究表明，硬化的间质可以促进多种肿瘤的转移。然而，在转移性肝癌中，肺机械微环境如何有利于循环中的肿瘤细胞仍不清楚。在这里，我们发现细胞迁移诱导的透明质酸结合蛋白(CEMIP)的表达与肺转移密切相关，并可以通过增加肺基质硬度来促进转移前生态位的形成。此外，血清CEMIP升高预示着肝细胞癌肺转移患者肺纤维化的严重程度。通过直接靶向CEMIP，吡非尼酮可以抑制CEMIP/转化生长因子-β-1/Smad信号通路，减少肺转移瘤的僵硬，显示出良好的抗肿瘤活性。吡非尼酮联合索拉非尼较单用索拉非尼能更有效地抑制肺转移的发生。本研究是首次尝试调节肝细胞癌治疗的机械微环境，并强调CEMIP是预防和治疗肝细胞癌肺转移的潜在靶点。同时，Pirfenidone可通过直接靶向CEMIP，降低转移僵硬，增强索拉非尼的抗血管生成作用。
Hepatocellular carcinoma (HCC) with lung metastasis is associated with poor prognosis and poor therapeutic outcomes. Studies have demonstrated that stiffened stroma can promote metastasis in various tumors. However, how the lung mechanical microenvironment favors circulating tumor cells remains unclear in metastatic HCC. Here, we found that the expression of cell migration-inducing hyaluronan-binding protein (CEMIP) was closely associated with lung metastasis and can promote pre-metastatic niche formation by increasing lung matrix stiffness. Furthermore, upregulated serum CEMIP was indicative of lung fibrotic changes severity in patients with HCC lung metastasis. By directly targeting CEMIP, pirfenidone can inhibit CEMIP/TGF-β1/Smad signaling pathway and reduce lung metastases stiffening, demonstrating promising antitumor activity. Pirfenidone in combination with sorafenib can more effectively suppress the incidence of lung metastasis compared with sorafenib alone. This study is the first attempt to modulate the mechanical microenvironment for HCC therapy and highlights CEMIP as a potential target for the prevention and treatment of HCC lung metastasis.CEMIP mediating an HCC-permissive microenvironment through controlling matrix stiffness. Meanwhile, Pirfenidone could reduce metastasis stiffness and increases the anti-angiogenic effect of Sorafenib by directly targeting CEMIP.
登录
查看更多内容
影响因子：
4.7
作者：
Joyce MH;Lu C;James ER;Hegab R;Allen SC;Suggs LJ;Brock A
通讯作者：
Brock A
影响因子：
3.7
作者：
Matsuzaki, Shinji;Tanaka, Fumiaki;Mori, Masaki
通讯作者：
Mori, Masaki
影响因子：
21.3
作者：
Costa-Silva B;Aiello NM;Ocean AJ;Singh S;Zhang H;Thakur BK;Becker A;Hoshino A;Mark MT;Molina H;Xiang J;Zhang T;Theilen TM;García-Santos G;Williams C;Ararso Y;Huang Y;Rodrigues G;Shen TL;Labori KJ;Lothe IM;Kure EH;Hernandez J;Doussot A;Ebbesen SH;Grandgenett PM;Hollingsworth MA;Jain M;Mallya K;Batra SK;Jarnagin WR;Schwartz RE;Matei I;Peinado H;Stanger BZ;Bromberg J;Lyden D
通讯作者：
Lyden D
DOI：
10.1146/annurev-bioeng-071813-105259
发表时间：
2014-07-11
影响因子：
9.7
作者：
Jain RK;Martin JD;Stylianopoulos T
通讯作者：
Stylianopoulos T
影响因子：
158.5
作者：
Finn, Richard S.;Qin, Shukui;Cheng, Ann-Lii
通讯作者：
Cheng, Ann-Lii