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

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.

Long non-coding RNA PVT1 encapsulated in bone marrow mesenchymal stem cell-derived exosomes promotes osteosarcoma growth and metastasis by stabilizing ERG and sponging miR-183-5p.

Exosomes secreted by bone marrow mesenchymal stem cells (BMSCs) promote osteosarcoma cell proliferation and migration, while the underlying mechanism remains unknown. Since the long non-coding RNA PVT1 has been reported to be upregulated in osteosarcoma cells and contributes to its growth and metastasis, we aim to investigate whether BMSC-derived exosomes promote osteosarcoma growth and metastasis via transporting PVT1 into osteosarcoma cells. The PVT1 expression in BMSC-derived exosomes was markedly higher than that in osteosarcoma cell-derived exosomes. The co-culturing of BMSC-derived exosomes and osteosarcoma cells (Saos-2, MG-63, and MNNG/HOS cell lines) significantly raised PVT1 expression of osteosarcoma cells. The direct binding between PVT1 and the oncogenic protein ERG was confirmed using RNA immunoprecipitation and RNA pull-down assays, and the transported PVT1 promotes osteosarcoma cell proliferation and migration via inhibiting degradation and ubiquitination of ERG. PVT1 also increased ERG expression through sponging miR-183-5p. In summary, our findings indicated that BMSC-derived exosomes encapsulate PVTl and transport it into osteosarcoma cells, and the transported PVT1 promotes tumor growth and metastasis by inhibiting ubiquitination and promoting expression of ERG in osteosarcoma cells. These data provide a novel insight into the mechanism of BMSC-derived exosomes in affecting osteosarcoma progression.