{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CDCA4, also known as Hepp, is a multifunctional cell cycle–associated protein that acts as a transcriptional coregulator and modulator of E2F‐dependent gene expression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " In normal cells, CDCA4 is expressed in a spatiotemporally restricted manner during embryogenesis and has been implicated in regulating cell cycle progression and differentiation. Its role in fine‐tuning E2F‐responsive promoter activity contributes to proper control of proliferation, as evidenced by the observation that alteration of CDCA4 levels (or its regulatory network) can affect DNA synthesis and cell growth.\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In oncogenic contexts, aberrant CDCA4 expression has been linked to tumor progression through multiple mechanisms. For example, RNA interference–mediated silencing of CDCA4 in human breast cancer cells resulted in reduced proliferation and increased apoptosis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", while in melanoma and lung adenocarcinoma cells, microRNAs such as miR‐15a and miR‐744‑5p target CDCA4 to modulate cell proliferation, migration, and invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In addition, studies in osteosarcoma and in the context of polycystic ovary syndrome (PCOS) have demonstrated that competing endogenous RNA networks involving miR‑503‑5p and Long Intergenic Noncoding RNA LINC02381 regulate CDCA4 expression, thereby modulating Rb/E2F1 signaling and thus influencing cell cycle progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its transcriptional regulatory role, CDCA4 has been implicated in mitotic processes. Its transient localization at spindle poles and midzone during metaphase and anaphase suggests a role in proper spindle organization, chromosome segregation, and cytokinesis; depletion of CDCA4 was associated with abnormal spindle formation and the appearance of multinucleated cells, which may contribute to cell cycle deregulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Clinically, elevated CDCA4 expression is frequently correlated with poorer patient outcomes in several malignancies. For instance, overexpression of CDCA4 has been linked to adverse prognostic markers in Wilms’ tumor"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", hepatocellular carcinoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", gastric cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", and head and neck squamous cell carcinoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " In lung cancer, conflicting roles have been described: while one study indicates that downregulation of CDCA4 (via miR‑15a or other noncoding RNAs) is linked with increased migration and invasion, another study suggests that overexpression of CDCA4 can counteract the tumor‐suppressive effects of specific long noncoding RNAs, thereby promoting malignancy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Moreover, CDCA4 is included in gene signatures that relate to energy metabolism and aggressive tumor behavior."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, CDCA4 function extends into early developmental stages, as indicated by its dynamic regulation in mouse early embryos where it is a predicted target of miR‑154, highlighting its contribution to the fine regulation of cell cycle events during embryogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies underscore the multifaceted role of CDCA4 in regulating transcriptional activation/suppression, spindle organization, and cell cycle progression. Dysregulation of CDCA4 contributes to oncogenesis and tumor progression, rendering it a promising prognostic biomarker and potential therapeutic target in diverse cancers.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Reiko Hayashi, Yuya Goto, Ryuji Ikeda, et al. 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