{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nProgrammed cell death protein 4 (PDCD4) is a multifaceted tumor suppressor that exerts its inhibitory effects partly by impairing the initiation of translation. PDCD4 binds directly to the RNA helicase eIF4A through its MA‐3 domains, thereby blocking the unwinding of structured 5′‐UTRs and preventing the incorporation of eIF4A into the eIF4F complex. Structural and biochemical studies have revealed that PDCD4’s interaction with eIF4A not only traps the helicase in an inactive conformation but also displaces essential co‐factors—mechanisms that account for its direct suppression of cap‐dependent protein synthesis and of key oncogenic transcripts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "t", "text": "\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in translational inhibition, PDCD4 functions as a critical mediator of anti‐tumorigenic signals by promoting apoptosis and suppressing invasive behavior. Through transcriptional regulatory effects—such as the indirect repression of pro‐mitotic genes via p21 upregulation and blockade of AP‐1–dependent gene activation—PDCD4 limits neoplastic transformation and cell cycle progression. Its loss, whether by proteasomal degradation induced by upstream kinases or other mechanisms, has been associated with enhanced invasion, metastasis, and dysregulated cellular homeostasis in diverse tumors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "18"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "t", "text": "\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA major layer of PDCD4 regulation occurs at the post‐transcriptional level through its targeted repression by oncogenic microRNAs—most notably miR‐21, but also miR‐182 and others. Overexpression of miR‐21 in various tumor types (including breast, glioblastoma, cholangiocarcinoma, cervical, colorectal, ovarian, pancreatic, renal, and esophageal cancers) leads to translational suppression of PDCD4, thereby facilitating enhanced cell proliferation, invasion, chemoresistance, and metastatic dissemination. Moreover, PDCD4 downregulation via microRNA action has been linked to aberrant signaling in the tumor microenvironment, with exosome‐mediated transfer of miR‐21 and dysregulation by long noncoding RNAs further contributing to the loss of PDCD4 function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "39"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "t", "text": "\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence further indicates that PDCD4 plays roles beyond direct tumor suppression. In settings of chronic inflammation, fibrogenesis, and immune activation, PDCD4 modulates inflammatory signaling pathways and apoptotic responses. Studies have shown that in immune cells and tissues—from natural killer lymphomas and glioblastomas to pulmonary and hepatic models—alterations in PDCD4 levels (often mediated by miR‐21 and associated RNA–protein interactions) are linked to shifts in cytokine production, innate immune responses, and even the expansion of regulatory T cells. Novel layers of regulation by long noncoding RNAs and through exosomal transfer underscore its importance as an integrative node connecting oncogenic signals, translational control, and the inflammatory milieu."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "40", "end_ref": "45"}]}, {"type": "t", "text": "\n\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hsin-Sheng Yang, Myung-Haing Cho, Halina Zakowicz, et al. 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