LINC00942 inhibits ferroptosis and induces the immunosuppression of regulatory T cells by recruiting IGF2BP3/SLC7A11 in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a common malignant tumor with a high recurrence rate and a poor prognosis. Long intergenic nonprotein coding RNA 942 (LINC00942) is reported to be related to ferroptosis and the immune response in HCC and serves as an oncogene in various cancers. This research aimed to explore the contribution of LINC00942 in HCC progression. Functional assays were used to evaluate the functional role of LINC00942 in vitro and in vivo. Mechanistic assays were conducted to assess the association of LINC00942 with insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) and solute carrier family 7 member 11 (SLC7A11) and the regulatory pattern of LINC00942 in HCC cells. LINC00942 was found to exhibit upregulation in HCC tissue and cells. LINC00942 facilitated HCC cell proliferation, suppressed ferroptosis, and converted naive CD4+ T cells to inducible Treg (iTreg) cells by regulating SLC7A11. Furthermore, SLC7A11 expression was positively modulated by LINC00942 in HCC cells. IGF2BP3 was a shared RNA-binding protein (RBP) for LINC00942 and SLC7A11. The binding between the SLC7A11 3′ untranslated region and IGF2BP3 was verified, and LINC00942 was found to recruit IGF2BP3 to promote SLC7A11 mRNA stability in an m6A-dependent manner. Moreover, mouse tumor growth and proliferation were inhibited, and the number of FOXP3+CD25+ T cells was increased, while ferroptosis was enhanced after LINC00942 knockdown in vivo. LINC00942 suppresses ferroptosis and induces Treg immunosuppression in HCC by recruiting IGF2BP3 to enhance SLC7A11 mRNA stability, which may provide novel therapeutic targets for HCC.

Causal effect between immunocytes, plasma metabolites, and hepatocellular carcinoma: a bidirectional two-sample Mendelian randomization study and mediation analysis

“…Previous outcomes might be triggered by some common confounders shared by HCC and IgD-CD27-AC. Jin et al explored that long intergenic nonprotein coding RNA 942 promotes HCC cell proliferation and converts naive CD4 T cells into inducible Treg (iTreg) cells by regulating solute carrier family 7 member 11, suggesting a protective role for naive CD4 + T cells in HCC pathogenesis [52]. Moreover, it has been found that the knockdown of Tubulin γ-1 (TUBG1) has been shown to inhibit the proliferation, invasion, and migration of HCC cells and TUBG1 expression was negatively correlated with CD4 + regulatory T-cell [53], which is in line with our MR results and supports a causal relationship.…”