{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC34A2 encodes the type IIb sodium–phosphate cotransporter (NaPi‐IIb), a key mediator of phosphate homeostasis in several organs—most notably in the lung. Loss‐of‐function mutations in SLC34A2 impair phosphate clearance in alveolar type II cells, resulting in the pathological deposition of calcium phosphate microliths observed in pulmonary alveolar microlithiasis (PAM). Genetic analyses in both familial and sporadic cases of PAM have uncovered a spectrum of mutations (including frameshifts, nonsense mutations, and promoter deletions) that abrogate normal protein function, thereby underlining the indispensable role of SLC34A2 in maintaining alveolar phosphate balance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its fundamental role in phosphate transport, aberrant expression of SLC34A2 has been implicated in the pathogenesis of diverse malignancies. In non–small cell lung cancer, for example, microRNA‐mediated suppression of SLC34A2 leads to activation of the Wnt/β–catenin cascade and enhanced tumor cell growth and invasion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": " In breast cancer, upregulation of SLC34A2 in cancer stem cell subpopulations not only potentiates chemoresistance via a SLC34A2–Bmi1–ABCC5 axis but also sustains stemness through PI3K/AKT/SOX2 signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "17"}]}, {"type": "t", "text": " Similarly, elevated SLC34A2 expression has been reported in thyroid cancers"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ", as well as in ovarian malignancies where it appears associated with tumor development and metastasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "23"}]}, {"type": "t", "text": " In colorectal cancer, deregulated SLC34A2 promotes cell proliferation and chemoresistance"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "26"}]}, {"type": "t", "text": ", while its overexpression has also been linked to hepatocellular"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": ", bladder"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": ", gastric"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": ", glioma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "30"}]}, {"type": "t", "text": ", neuroblastoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "31"}]}, {"type": "t", "text": ", and esophageal cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "32"}]}, {"type": "t", "text": " Moreover, aberrant SLC34A2 expression may contribute to the transformation of alveolar type II cells by facilitating malignant conversion toward adenocarcinoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistic studies on SLC34A2 have further uncovered its involvement in key regulatory networks that modulate tumor progression and normal cellular physiology. Investigations into antibody–drug conjugates directed against NaPi–IIb highlight the translational potential of SLC34A2 as a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "34"}]}, {"type": "t", "text": " Detailed analyses of the hNaPi–IIb gene promoter have revealed critical cis–acting elements and transcription factor binding—underscoring the fine regulation of phosphate transport."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": " In addition, signaling studies have implicated the SPAK/OSR1 kinases in governing NaPi–IIb activity"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "36"}]}, {"type": "t", "text": ", while investigations into sodium–lithium countertransport have linked SLC34A2 variants to ion transport regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "37"}]}, {"type": "t", "text": " Complementary work on the impact of pathogenic variants further emphasizes how specific mutations modulate transporter expression and function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "38", "end_ref": "40"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ayse Corut, Abdurrahman Senyigit, Sibel Aylin Ugur, et al. 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