Overexpression of the transcribed ultraconserved region Uc.138 accelerates colon cancer progression

Abstract

Ultraconserved regions (UCRs) are 481 genomic sequences with 100% identity across humans, rats, and mice. Increasing evidence suggests that non-coding RNAs transcribed from UCRs are involved in various diseases, especially cancers. The human transformer 2β gene (TRA2B) encodes a UCR (uc.138) that spans exon 2 and its neighboring introns. TRA2B4 RNA is the only transcript that contains the whole exon 2 among five spliced TRA2B RNA variants (TRA2B1-5). TRA2B4 is upregulated in colon cancer cell lines, although it is not translated to Tra2β protein because of its nuclear retention. Nevertheless, the clinical significance and biological functions of uc.138 in colon cancer cells remain unclear. In this study, RNA in situ hybridization showed that TRA2B4 was predominantly overexpressed in the nucleus of colon adenocarcinoma and adenoma. Overexpression of TRA2B4 in colon cancer HCT116 cells promoted cell proliferation by changing the expression of G2/M-related cell cycle regulators. Moreover, TRA2B4 increased migration and cell viability in a uc.138 sequence-dependent manner. TRA2B4 significantly enhanced tumorigenesis in vivo. Taken together, uc.138 encoded in TRA2B4 plays an oncogenic role in tumor progression and may become a potential biomarker and therapeutic target in colon cancer.

Transcribed Ultraconserved Regions Are Associated with Clinicopathological Features in Breast Cancer

“…In luminal B patients, high expression is associated with better survival, but this association is not seen in PFI. Uc.138 was previously associated with tumors, but in colon cancer [ 35 , 36 ]. In contrast with our observation in breast cancer, uc.138 is overexpressed and associated with a poor prognosis in colon cancer cases [ 36 ].…”

“…Uc.138 was previously associated with tumors, but in colon cancer [ 35 , 36 ]. In contrast with our observation in breast cancer, uc.138 is overexpressed and associated with a poor prognosis in colon cancer cases [ 36 ]. In colon cells, the transcript containing uc.138 is nuclear and influences cell proliferation by changing the expression of G2/M-related cell cycle regulators.…”

Ultra-conserved RNA: a novel biological tool with diagnostic and therapeutic potential

“…It was identified that overexpression of uc.138 can increase cell proliferation by increasing G2 and S phases-related gene expression, including CDK1, cyclin A, and cyclin B and by downregulating genes related to cell death to reduce apoptosis. Consequently, this results in the resistance of colon cancer cells to anticancer drugs and promotes the migration of tumor cells [ 45 ]. In another study, uc.77- inhibited the growth of colorectal cancer (CRC) cells by blocking the G0/G1 phase through downregulation of the CDK4 protein (affected by E3 ligase).…”

Transcribed Ultraconserved Regions: New regulators in cancer signaling and potential biomarkers

“…In a recent study of HCC cells, the overexpression of TRA2B4 or exon 2 increased the percentage of G2/M cells and deregulated expression of cell-cycle related gene in a concordant manner. After 5-fluorouracil or Adriamycin treatment, the overexpression of TRA2B4 increased viability, associating this T-UCR also with drug resistance ( Kuwano et al, 2021 ). Additionally, increased migration, and enhanced tumorigenesis in vivo after overexpression reinforcing the point that Uc.138/TRA2β4 transcript plays an oncogenic role in tumor progression ( Kuwano et al ., 2021 ).…”

“…After 5-fluorouracil or Adriamycin treatment, the overexpression of TRA2B4 increased viability, associating this T-UCR also with drug resistance ( Kuwano et al, 2021 ). Additionally, increased migration, and enhanced tumorigenesis in vivo after overexpression reinforcing the point that Uc.138/TRA2β4 transcript plays an oncogenic role in tumor progression ( Kuwano et al ., 2021 ). It is interesting to note that Uc.138 contains a stem-loop structure (449-488 nt) and the introduction of mutations in the stem-loop motif canceled these effects, thus showing the importance of UCR sequence in TRA2β4 transcript role ( Kuwano et al ., 2021 ).…”