RARRES1 inhibits hepatocellular carcinoma progression and increases its sensitivity to lenvatinib through interaction
Yarong Guo1,2, Bao Chai3, Hezhao Zhang4
1Department of Digestive System Oncology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, 030032, Taiyuan, Shanxi, China.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
RARRES1 and SPINK2 act as tumor suppressors in hepatocellular carcinoma (HCC). Their interaction enhances lenvatinib sensitivity, offering a new therapeutic strategy for HCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Hepatocellular Carcinoma Research
Background:
- Lenvatinib is an oral small molecule inhibitor for unresectable hepatocellular carcinoma (HCC).
- Enhancing lenvatinib sensitivity is crucial for improving therapeutic efficacy in HCC patients.
Purpose of the Study:
- To identify genes influencing lenvatinib sensitivity in HCC.
- To elucidate the mechanism by which these genes affect HCC progression and lenvatinib response.
Main Methods:
- High-throughput screening identified differentially expressed genes (DEGs) related to lenvatinib sensitivity.
- Gain- and loss-of-function experiments assessed gene roles in HCC and lenvatinib sensitivity.
- Co-immunoprecipitation (CO-IP) and rescue experiments investigated molecular mechanisms.
Main Results:
- RARRES1 (RAR responder protein 1) was upregulated by lenvatinib and suppressed HCC progression, enhancing sensitivity.
- RARRES1 interacted with SPINK2 (serine protease inhibitor Kazal-type 2), which also inhibited HCC progression and increased lenvatinib sensitivity.
- Both RARRES1 and SPINK2 were downregulated in HCC tissues compared to normal liver tissues.
Conclusions:
- A novel tumor suppressor axis, RARRES1/SPINK2, was identified in HCC.
- This axis inhibits HCC progression and modulates lenvatinib sensitivity, presenting a potential therapeutic target.
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