Roles of lncRNA LVBU in regulating urea cycle/polyamine synthesis axis to promote colorectal carcinoma progression

Abstract

Altered expression of Urea Cycle (UC) enzymes occurs in many tumors, resulting a metabolic hallmark termed as UC dysregulation. Polyamines are synthesized from ornithine, and polyamine synthetic genes are elevated in various tumors. However, the underlying deregulations of UC/ polyamine synthesis in cancer remain elusive. Here, we characterized a hypoxia-induced lncRNA LVBU (lncRNA regulation via BCL6/urea cycle) that is highly expressed in colorectal cancer (CRC) and correlates with poor cancer prognosis. Increased LVBU expression promoted CRC cells proliferation, foci formation and tumorigenesis. Further, LVBU regulates urea cycle and polyamine synthesis through BCL6, a negative regulator of p53. Mechanistically, overexpression of LVBU competitively bound miR-10a/miR-34c to protect BCL6 from miR-10a/34c-mediated degradation, which in turn allows BCL6 to block p53-mediated suppression of genes (arginase1 ARG1, ornithine transcarbamylase OTC, ornithine decarboxylase 1 ODC1) involved in UC/polyamine synthesis. Significantly, ODC1 inhibitor attenuated the growth of patient derived xenografts (PDX) that sustain high LVBU levels. Taken together, elevated LVBU can regulate BCL6-p53 signaling axis for systemic UC/polyamine synthesis reprogramming and confers a predilection toward CRC development. Our data demonstrates that further drug development and clinical evaluation of inhibiting UC/polyamine synthesis are warranted for CRC patients with high expression of LVBU.

CircRNA_0000927 promotes inflammatory response to neuronal injury via miR-126a-5p/PGC-1α axis in acute ischemic stroke

“…The potential clinical application prospect of circRNA is huge (Liang et al, 2022). CircRNA is often abnormally expressed and expressed in cerebrovascular disease and high tissue speci city (Meng et al, 2022). Therefore, targeted therapy targeting circRNA may be developed into a new way to treat cerebrovascular disease in the future, and theoretically, it may not cause the harmful side effects to healthy tissues (Miozzo et al, 2022).…”

“…Recent ndings have also con rmed that circRNA has a variety of biological functions, including regulating the chromosome recombination, controlling the gene transcription, pre-transcription mRNA processing, and affecting the protein signal function and localization (Liang et al, 2022). CircRNAs involved in stroke also have a wide range of mechanisms, including DNA inactivation, methylation, transcriptional promotion, activation of other RNA molecules, and so on (Bauer et al, 2022;Meng et al, 2022). Moreover, scientists have found that circRNA can undergo various epigenetic modi cations, including methylation and ubiquitination, and act as ceRNA with some microRNAs (miRNAs) to form a regulatory network (Siegerist et al, 2021).…”

eIF3f Mediates SGOC Pathway Reprogramming by Enhancing Deubiquitinating Activity in Colorectal Cancer

“…Luciferase Reporter Assay: Luciferase reporter assay was performed as previously described. [44] Basically, cells seeded in 24-well plates were transfected with indicated amount of pGL3 or pGL3-pEIF3F containing a TCF7L2 transcription factor binding site on EIF3F, pRL-CMV, and pCMV-MYC-TCF7L2 expressing plasmid into HEK293T cells. After 48 h, cells were lysed, and the reporter activity was assayed with the dual luciferase assay system (Promega, #E1960) according to the manufacturer's instructions.…”

Patient‐derived xenograft model in colorectal cancer basic and translational research

“…Hypoxia‐induced exosomal miR‐135a‐5p is involved in the development, clinical severity, and prognosis of CRC liver metastases through the pre‐metastatic niche 134 . LncRNA LVBU promotes CRC progression by regulating urea cycle/polyamine synthesis axis 135 . These papers studied the mechanism of CRC metastasis using the PDX model.…”

“… 134 LncRNA LVBU promotes CRC progression by regulating urea cycle/polyamine synthesis axis. 135 These papers studied the mechanism of CRC metastasis using the PDX model. Overall, PDX models are becoming more common in CRC basic research.…”