{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nProtein kinase C iota (PRKCI) functions as an oncogenic driver in multiple tumor types by promoting cellular transformation, self‐renewal and stem‐like phenotypes. In lung squamous cell carcinoma, PRKCI cooperates with SOX2 by phosphorylating it to enhance transcription of key Hedgehog pathway genes, thereby maintaining stem‐like properties (1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In lung adenocarcinoma, an alternatively spliced circular RNA transcribed from the PRKCI locus (circPRKCI) acts as a microRNA sponge to derepress oncogenic transcription factors (2."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In addition, PRKCI is genomically amplified and overexpressed in ovarian, lung and colon cancers, where it is essential for anchorage‐independent growth, transformation downstream of oncogenic Ras and in Rac1–Pak–MEK/ERK signaling (3"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "; 5"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "; 7"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "; 8"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "; 20"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "; 26."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in oncogenesis, PRKCI is pivotal in the regulation of epithelial cell polarity and cytoskeletal dynamics. It partners with polarity regulators such as Par6 and Ect2 to control mitotic spindle orientation, apical membrane formation, and tight junction organization, thereby contributing to proper epithelial morphogenesis (10"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "; 11."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Moreover, in basal cell carcinoma PRKCI functions as a downstream effector of Hedgehog signaling, phosphorylating GLI1 to potentiate transcriptional activation (4."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Its regulatory influence extends to the cytoskeleton through phosphorylation of ezrin and calpain enzymes, thereby modulating cell migration and invasion (9"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "; 12."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " PRKCI also collaborates with its binding partners and downstream effectors—in some contexts controlling transcription factors like Sp1, Cyclin E, and YAP1—to impact proliferative and invasive behaviors, as well as to modify cell–cell adhesion components (13"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "; 14"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "; 15"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "; 16"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "; 17."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSystem‐level analyses further reveal that PRKCI signaling intersects with metabolic and immune pathways to shape the tumor microenvironment and influence therapeutic responses. In neuroendocrine prostate cancer, for instance, reduced PRKCI expression redirects metabolic flux and epigenetic reprogramming, underscoring its context‐dependent roles (6."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " In lung, ovarian and other cancers, PRKCI is targeted by emerging therapies such as aurothiomalate and auranofin, which disrupt its oncogenic signaling cascades that include the Par6–Ect2–Rac1 axis (18"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "; 19"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "; 21."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": " Moreover, by modulating transcriptional regulators such as YAP1, PRKCI contributes to the establishment of an immunosuppressive microenvironment that hinders cytotoxic T‐cell infiltration, while its structural features have been elucidated to inform rational drug design (22"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "; 23"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "; 24"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": "; 25"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": "; 27"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": "; 28"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": "; 29"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": "; 30"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "30"}]}, {"type": "t", "text": "; 31"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "31"}]}, {"type": "t", "text": "; 32"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "32"}]}, {"type": "t", "text": "; 33"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "33"}]}, {"type": "t", "text": "; 34"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "34"}]}, {"type": "t", "text": "; 35."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Verline Justilien, Michael P Walsh, Syed A Ali, et al. 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