{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Long intergenic non‐protein coding RNA 00346 (LINC00346) has emerged as a multifunctional regulator in diverse human diseases, particularly in cancer. Elevated levels of LINC00346 have been detected in several malignancies—including breast cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ", pancreatic cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", pancreatic ductal adenocarcinoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", bladder cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", cutaneous squamous cell carcinoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", non‐small cell lung cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "and hepatocellular carcinoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In these tumors its upregulation often correlates with poor overall survival, advanced clinicopathological features, and chemoresistance.\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In pancreatic cancer, for example, LINC00346 promotes cell proliferation, colony formation, tumorigenesis, and gemcitabine resistance by acting as a competing endogenous RNA (ceRNA) that sequesters microRNAs such as miR‐188‐3p—thereby upregulating targets like BRD4."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In another pancreatic study, elevated LINC00346 expression was associated with advanced clinical stage and reduced patient survival"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", and it was also incorporated into a prognostic risk score system."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In pancreatic ductal adenocarcinoma, LINC00346 facilitates tumor aggressiveness by interacting with the transcriptional repressor CTCF, which leads to de‐repression of c‐Myc."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In bladder cancer, knockdown of LINC00346 impairs cell proliferation and migration while inducing apoptosis, suggesting an oncogenic function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Similarly, in non‐small cell lung cancer, LINC00346 overexpression promotes proliferation and survival via modulation of the JAK–STAT3 signaling pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Hepatocellular carcinoma (HCC) studies have revealed that LINC00346 functions within ceRNA networks—sponging microRNAs such as miR‑542‑3p and miR‑199a‑3p—to upregulate oncogenes involved in cell cycle progression (e.g. CDK1/CCNB1) and to activate pathways like Wnt/β‐catenin."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}, {"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In breast cancer, beyond its association with poor outcome"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ", LINC00346 regulates tumor cell glycolysis by sponging miR‑148a/b, leading to upregulation of GLUT1 and increased glucose uptake and lactate production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In cutaneous squamous cell carcinoma, LINC00346 (also referred to as PRECSIT) is negatively regulated by p53; its overexpression activates STAT3 signaling and matrix metalloproteinase expression to promote invasion and tumor growth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In glioma, multiple reports indicate that LINC00346 acts as an oncogenic ceRNA. It sponges microRNAs such as miR‑128‑3p and miR‑340‑5p to upregulate targets including SZRD1, ROCK1, and, via additional mechanisms, modulate angiogenesis through STAU1-mediated degradation of ZNF655 mRNA."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "16"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, in nasopharyngeal carcinoma, LINC00346 contributes to cisplatin resistance by targeting miR‑342‑5p"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", and in gastric cancer, its amplification and overexpression correlate with advanced stage and poor prognosis via sponging of miR‑34a‑5p to modulate oncogenic proteins such as CD44, NOTCH1 and AXL."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Additional studies have implicated LINC00346 in colorectal cancer stem cell maintenance through the miR‑509‑5p/WBSCR22 axis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "and in lung adenocarcinoma where it acts as an oncogenic ceRNA to accelerate tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": " Beyond oncogenesis, LINC00346 has also been linked to pathological processes in non‐malignant conditions. For instance, it participates in a KLF5/LINC00346/miR‑148a‑3p regulatory loop that exacerbates endothelial inflammation and injury in atherosclerosis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", and its dysregulated expression in schizophrenia suggests a potential role in neuropsychiatric conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings highlight that LINC00346 functions predominantly as an oncogenic lncRNA—modulating cell proliferation, migration, invasion, apoptosis, metabolism and chemoresistance—through diverse molecular mechanisms that mainly involve acting as a competing endogenous RNA to deregulate tumor‐promoting genes. This multifaceted regulatory capacity makes LINC00346 a promising prognostic biomarker and a potential therapeutic target in a wide range of human cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hairong Liu, Juan Li, Pratirodh Koirala, et al. 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