{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nOVAAL, a long noncoding RNA, is upregulated in several cancers and contributes to tumor progression by promoting cell proliferation and survival. In particular, OVAAL interacts directly with serine/threonine-protein kinase 3 (STK3) to enhance its association with Raf-1, thereby activating the RAF/MEK/ERK signaling cascade. This activation leads to increased c-Myc‐dependent transcription and Mcl-1–mediated cell survival. Moreover, OVAAL suppresses cellular senescence by competitively sequestering PTBP1 away from p27 mRNA, thus preventing p27 upregulation. The transcription of OVAAL itself is driven by c-Myc, forming a positive feedback loop that further reinforces tumor cell proliferation and apoptotic resistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n\nIn gastric cancer, OVAAL has been shown to be markedly upregulated and is associated with poor prognosis and resistance to 5-fluorouracil (5-FU) chemotherapy. Mechanistically, OVAAL binds to pyruvate carboxylase (PC) and prevents its degradation via the HSC70/CHIP-mediated ubiquitination pathway. This stabilization of PC leads to increased intracellular levels of oxaloacetate and aspartate, thereby enhancing pyrimidine biosynthesis. The augmented pyrimidine production counteracts the thymidylate synthase dysfunction induced by 5-FU, ultimately promoting cell proliferation and chemoresistance. Conversely, knockdown of OVAAL results in diminished pyrimidine synthesis and increased sensitivity to 5-FU, which can be rescued by PC overexpression or metabolite repletion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n\nTogether, these studies highlight the dual role of OVAAL in mediating both apoptotic resistance and metabolic reprogramming to foster cancer cell survival and chemoresistance, identifying it as a promising therapeutic target in multiple malignancies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ben Sang, Yuan Yuan Zhang, Su Tang Guo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dual functions for OVAAL in initiation of RAF/MEK/ERK prosurvival signals and evasion of p27-mediated cellular senescence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1805950115"}], "href": "https://doi.org/10.1073/pnas.1805950115"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30478051"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30478051"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jia-Nan Tan, Sheng-Ning Zhou, Wei Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Long noncoding RNA OVAAL enhances nucleotide synthesis through pyruvate carboxylase to promote 5-fluorouracil resistance in gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cas.15453"}], "href": "https://doi.org/10.1111/cas.15453"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35657686"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35657686"}]}]}]}