HBV HBx-Downregulated lncRNA LINC01010 Attenuates Cell Proliferation by Interacting with Vimentin

Abstract

Hepatitis B virus (HBV) infection is closely related to hepatocellular carcinoma (HCC) development. To investigate the mechanism of HBV causing HCC, we previously analyzed the transcription of the HBV-transgenic cell line HepG2-4D14 and parental HepG2 cells and identified a subset of long noncoding RNAs (lncRNAs) differentially expressed between them. In this study, we focus on lncRNA LINC01010, as it is significantly downregulated in HepG2-4D14 cells and in liver tissues of HCC patients, and positively correlated with survival. We found that HBV-encoded HBx can reduce the transcription of LINC01010. Functional analysis showed that the overexpression of LINC01010 inhibits proliferation, migration and invasion of HepG2 cells while the knockdown of LINC01010 promotes these processes. By taking the approach of RNA immunoprecipitation (RIP) and mass spectrometry, we identified that LINC01010 can interact with vimentin. Further studies demonstrated that LINC01010 negatively affects the vimentin network extension and causes more rapid subunit exchange and lower stability of vimentin filaments. In addition, LINC01010 can reduce the amount of insoluble vimentin within cells, which suggests that LINC01010 interfers with vimentin polymerization. These data indicate that LINC01010 can inhibit the assembly of vimentin filament. Thus, we revealed that HBV HBx-downregulated LINC01010, which suppresses cell proliferation and migration by negatively regulating the formation of vimentin filament. Taken together, LINC01010 is a potential tumor suppressor that may restrain HBV-related HCC development.

A double-edged sword: The HBV-induced non-coding RNAs alterations in hepatocellular carcinoma

“…In most cases, HBV alters the non-coding RNA expression to elevate the expression levels of oncogenic genes, thus leading to the development of cancer. But several studies have reported the suppressive effect of non-coding RNAs on HCC development (Deng et al, 2020;Gan et al, 2021). Another mechanism of HBV infection-mediated repression of the development of HCC is by reducing the expression of miR-15a and miR-16-1.…”

The interplay of long noncoding RNAs and hepatitis B virus

“…115 4.7 | Long intergenic nonprotein coding RNA 1010 (LINC01010) LINC01010 is a transcript recently noted to be downregulated in lung, breast, and liver cancers. [116][117][118] Several groups have analyzed and reported on the positive correlation between LINC01010 expression and more favorable prognostic outcomes in these cancers as well as neuroblastomas, leading to hypotheses that it may function as a tumor suppressor. [116][117][118][119] Considering that LINC01010 is expressed at significantly lower levels in patient tumor tissue relative to normal tissue in The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort, one group aimed to further dissect the correlations between HBV and LINC01010 expression.…”

“…Considering that LINC01010 is expressed at significantly lower levels in patient tumor tissue relative to normal tissue in The Cancer Genome Atlas–Liver Hepatocellular Carcinoma (TCGA‐LIHC) cohort, one group aimed to further dissect the correlations between HBV and LINC01010 expression. 63 HCC patient samples were classified as either “high” or “low” HBV‐load groups based on copies of HBV in patient sera, and RT‐qPCR data demonstrated significantly lower amounts of LINC01010 in the high HBV‐load group relative to the low HBV‐load group 118 . Subsequent experiments demonstrated lower LINC01010 levels in L02 cells transfected with pcDNA3.1‐HBV1.3, which contains a replication‐competent copy of the HBV genome, versus pcDNA3.1 alone, and a HepG2‐GFP‐HBx stable cell line relative to HepG2‐GFP.…”

“…Subsequent experiments demonstrated lower LINC01010 levels in L02 cells transfected with pcDNA3.1‐HBV1.3, which contains a replication‐competent copy of the HBV genome, versus pcDNA3.1 alone, and a HepG2‐GFP‐HBx stable cell line relative to HepG2‐GFP. LINC01010 may regulate cell proliferation and invasion via interaction with vimentin, but further studies are needed to clarify its functions 118 …”

LncRNA SAMD12-AS1 Suppresses Proliferation and Migration of Hepatocellular Carcinoma via p53 Signaling Pathway

“…The LINC01010 interferes with vimentin polymerization and then inhibits the proliferation and migration ability of liver cancer cells. Thus, LINC01010 is a potential tumor suppressor that can inhibit HBV-related liver cancer development [ 12 ]. The lncRNA SAMD12-AS1 is a new cancer-promoting lncRNA, and its function is less studied.…”