RARRES1 inhibits hepatocellular carcinoma progression and increases its sensitivity to lenvatinib through interaction with SPINK2

• Published in: Biology direct 2024-02, Vol.19 (1), p.15-15, Article 15
• Main Authors: Guo, Yarong, Chai, Bao, Zhang, Hezhao, Chai, Xinhao, Chen, Yan, Xu, Jun, Qin, Liwei, Chai, Yuting
• Format: Article
• Language: English
• Subjects: Apoptosis; Cancer therapies; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Care and treatment; Cell adhesion & migration; Cell cycle; Cell growth; Cell Line, Tumor; Cell migration; Cell proliferation; Diagnosis; Functional analysis; Hepatocellular carcinoma; Hepatoma; Humans; Immunoprecipitation; Kinases; Lenvatinib; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Membrane Proteins - metabolism; Metabolism; mRNA; Phenylurea Compounds - pharmacology; Phenylurea Compounds - therapeutic use; Protease inhibitors; Proteinase inhibitors; Proteins; Quinolines; RARRES1; Sensitivity; Serine proteinase; Serine Proteinase Inhibitors - therapeutic use; SPINK2; Tumor suppressor genes; Tumors
• ISSN: 1745-6150; 1745-6150
• DOI: 10.1186/s13062-024-00459-0

Lenvatinib is an oral small molecule inhibitor approved for treating patients with unresectable hepatocellular carcinoma (HCC) worldwide. Increasing cell sensitivity to lenvatinib would be an effective method of improving therapeutic efficacy. High throughput methods was used to scan the differentially expressed genes (DEGs) related to lenvatinib sensitivity in HCC cells. Gain- and loss-function experiments were used to explore the functions of these DEGs in HCC and lenvatinib sensitivity. CO-IP assay and rescue experiments were utilized to investigate the mechanism. We identified that RAR responder protein 1 (RARRES1), a podocyte-specific growth arrest gene, was among significantly upregulated DEGs in HCC cells following lenvatinib treatment. Functional analysis showed that ectopic RARRES1 expression decreased HCC progression in vitro and in vivo, as well as improving tumor sensitivity to lenvatinib, while RARRES1 silencing increased HCC cell proliferation and migration. Mechanistically, co-immunoprecipitation assays demonstrated that RARRES1 interacted with serine protease inhibitor Kazal-type 2 (SPINK2) in HCC cells. Further, SPINK2 overexpression suppressed HCC cell proliferation and migration, as well as increasing sensitivity to lenvatinib whereas SPINK2 knockdown promoted cell progression and decreased lenvatinib sensitivity. The mRNA and protein levels of RARRES1 and SPINK2 were low in HCC tissue samples, relative to those in normal liver tissue. Our findings highlighted that RARRES1 can inhibit HCC progression and regulate HCC sensitivity to lenvatinib by interacting SPINK2, representing a new tumor suppressor RARRES1/SPINK2 axis in HCC that modulates sensitivity to lenvatinib.