Inhibition of CEMIP potentiates the effect of sorafenib on metastatic hepatocellular carcinoma by reducing the stiffness of lung metastases.
Mingyu LiuLulu XieYuying ZhangJianning ChenXiang ZhangYe ChenWensou HuangMingyue CaiLicong LiangMiaoling LaiJingjun HuangYongjian GuoLiteng LinKang-Shun ZhuPublished in: Cell death & disease (2023)
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.
Keyphrases
- poor prognosis
- signaling pathway
- squamous cell carcinoma
- idiopathic pulmonary fibrosis
- small cell lung cancer
- circulating tumor cells
- type diabetes
- long non coding rna
- cell migration
- cell proliferation
- oxidative stress
- metabolic syndrome
- adipose tissue
- transforming growth factor
- cancer therapy
- skeletal muscle
- risk assessment
- insulin resistance
- induced apoptosis
- human health
- bone marrow
- smoking cessation
- weight loss