{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n INSL4—also known as early placenta insulin‐like peptide (EPIL)—is a primate‐restricted member of the relaxin/insulin superfamily that is predominantly expressed in the placenta and uterus"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "and maps to chromosome 9p24."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In normal placental development its transcription is driven by a human endogenous retroviral element that confers a tightly controlled, placenta‐specific expression pattern, including alternative splice variants that may modulate trophoblast differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Functional studies in placental cell models have revealed that INSL4/EPIL possesses growth‐inhibitory properties by inducing apoptosis and reducing cell viability; indeed, increased INSL4 expression in placental tissues has been associated with higher levels of apoptosis and fetal growth restriction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": " In addition, distinct expression changes of INSL4 have been observed in abnormal placentation, such as the decreased levels in invasive trophoblasts of placenta accreta"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "and aberrant steroidogenic environments in preeclampsia, intrauterine growth restriction, and preterm labor."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its physiological role in placental development, emerging evidence indicates that INSL4 functions in oncogenesis. In LKB1‐deficient non–small cell lung cancers, INSL4 is dramatically induced through aberrant CRTC–CREB activation and supports tumor cell growth and survival, correlating with advanced stage, lymph node metastasis, and poorer overall survival."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": " Similarly, in HER‐2–positive breast cancers, overexpression of EPIL promotes the formation of cell protrusions, increases invasiveness, and is associated with reduced phosphorylation of key signaling molecules (Her2, ERK1/2, and AKT), ultimately correlating with significantly poorer five‐year survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In contrast, synthetic INSL4 peptides have been shown to lack activity at canonical relaxin receptors such as LGR7/GREAT/LGR8, suggesting that INSL4 signals via alternative, yet to be defined pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Epigenetic regulation appears to be a key mechanism controlling INSL4 expression; for example, hypomethylation of a retrotransposon‐derived promoter element is associated with its robust, placenta‐specific expression and may also contribute to overexpression in neoplastic tissues such as thyroid cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " Evolutionary analyses further indicate that INSL4 is among the more ancient members of the relaxin/insulin family; although lost in many mammalian lineages, it has been selectively retained in catarrhine primates."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, the development of sensitive immunoassays has enabled quantification of pro‐INSL4 (pro‐EPIL) peptides in amniotic fluid and maternal serum, revealing a dynamic pattern during gestation that parallels human chorionic gonadotropin (hCG) production and suggesting common regulatory pathways in embryonic and fetal development"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}, {"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", and further underscoring the functional significance of INSL4 in both reproductive physiology and pathology.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ivan Bièche, Anne Laurent, Ingrid Laurendeau, et al. 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