Olfactomedin-like 3: Possible Functions in Embryonic Development and Tumorigenesis
Introduction
Olfactomedin-like 3 (OLFML3), also known as hOLF44, is a secreted glycoprotein consisting of 406 amino acid residues. It belongs to the Olfactomedin (OLF) family, a group of proteins found across various species with significant roles in early development. The OLF family was first discovered in the olfactory epithelium of the bullfrog nearly 30 years ago, and since then, over 100 OLF members have been identified in species ranging from Caenorhabditis elegans to Homo sapiens. OLFML3 stands out due to its unique structure and differential expression patterns, which distinguish it from other members of the OLF family. This review explores the structure, expression, biological functions, and regulatory mechanisms of OLFML3, with a focus on its roles in embryonic development and tumorigenesis.
Structure of OLFML3
OLFML3 is encoded by a gene located on chromosome 1 (band P13.2) in humans. The gene consists of three exons and two introns, with all exon-intron junctions adhering to the GT/AG rule. The coding DNA sequence of OLFML3 spans 1221 nucleotides, flanked by untranslated regions (UTRs), and encodes a messenger RNA of 1852 nucleotides. The open reading frame of the gene produces a protein of 406 amino acid residues, with a predicted molecular weight of 44,000. The protein features a highly conserved C-terminal olfactomedin-like (OLF) domain and a more variable N-terminal coiled-coil domain. This structural configuration is highly conserved across species, with 94% similarity in polypeptide sequences between humans, cattle, mice, and rats. The OLF domain is particularly conserved, suggesting its importance in intracellular protein folding and accumulation.
Expression of OLFML3
OLFML3 exhibits differential expression across various tissues and organs. It is highly expressed in the placenta, moderately expressed in the heart and liver, and weakly expressed in skeletal muscle, small intestine, lung, and kidney. Very low expression is observed in the colon, spleen, thymus, and brain. In ocular tissues, OLFML3 is expressed in the cornea, lens, uvea, and retina. Notably, OLFML3 is absent in peripheral blood leukocytes. In the placenta, OLFML3 is predominantly expressed in syncytiotrophoblastic cells, with minimal expression in the maternal decidua layer, suggesting a potential role in fetal development. In microglia, OLFML3 is highly expressed in the cytoplasm and perinuclear endoplasmic reticulum, distinguishing it from other macrophage populations. During embryonic development, OLFML3 is detected in the axial and paraxial mesoderm, particularly in Hensen’s node in chick embryos. This expression pattern underscores its involvement in early developmental processes.
Biological Function and Regulation of OLFML3
OLFML3 plays a multifaceted role in biological processes, primarily in embryonic development and tumorigenesis. Its functions are mediated through interactions with extracellular matrix (ECM) components and signaling pathways such as Transforming Growth Factor beta 1 (TGFb1) and Bone Morphogenetic Protein 4 (BMP4).
Embryonic Development Related Function and Regulation
OLFML3 is crucial for the development of the central nervous system (CNS). It is involved in the maturation of microglia, immune cells that play a key role in CNS development. OLFML3 is upregulated by TGFb1/SMAD2 signaling during the early postnatal period, which is essential for the induction of immature microglia. This regulation is critical for establishing the microglial gene expression pattern, which is necessary for proper CNS function.
In skeletal muscle development, OLFML3 influences the formation of primary muscle fibers, which determine the total number of muscle fibers in adults. MicroRNA-155 (miRNA-155) has been identified as a regulator of OLFML3 expression in porcine prenatal muscle. miRNA-155 downregulates OLFML3 by targeting its 3’-UTR, leading to reduced muscle cell proliferation and altered postnatal muscle phenotype.
OLFML3 also plays a role in dorsal-ventral patterning during embryogenesis. In Xenopus and chicken embryos, OLFML3 enhances the degradation of chordin, a protein that inhibits BMP signaling. By facilitating the interaction between chordin and BMP1/Tolloid-class proteinases, OLFML3 ensures stable dorsal-ventral patterning. This function highlights its importance in early embryonic development.
Tumorigenesis, Metastasis, and Regulation
OLFML3 is implicated in tumor growth and metastasis through its roles in angiogenesis, anoikis resistance, and epithelial-to-mesenchymal transition (EMT). Angiogenesis, the formation of new blood vessels, is a critical process for tumor growth. OLFML3 promotes angiogenesis by signaling to both endothelial cells and pericytes, key components of the tumor vasculature. It interacts with BMP4, a pro-angiogenic factor, to enhance SMAD1/5/8 signaling, leading to vascular endothelial cell activation. This dual expression in endothelial cells and pericytes makes OLFML3 a potential therapeutic target for anti-angiogenic therapy.
Anoikis, a form of programmed cell death triggered by detachment from the ECM, is a critical barrier to tumor metastasis. OLFML3 promotes anoikis resistance in cancer cells, enabling them to survive in the absence of ECM attachment. High expression of OLFML3 is observed in anoikis-resistant cancer cell lines, including lung, nasal, and breast cancer cells. The mechanism by which OLFML3 prevents anoikis is not fully understood but may involve interactions with cell surface receptors or apoptotic machinery.
OLFML3 also plays a role in EMT, a process by which cancer cells acquire invasive properties. It is downregulated by the breast carcinoma metastasis suppressor gene 1 (BRMS1), which inhibits EMT and reduces metastasis. Additionally, OLFML3 is upregulated in carcinoma-associated fibroblasts (CAFs), which contribute to tumor progression and chemotherapy resistance. In head and neck cancer, OLFML3 expression increases following cetuximab treatment, suggesting its involvement in chemotherapy resistance.
OLFML3-Related Diseases
OLFML3 has emerged as a potential biomarker and therapeutic target in various diseases, including cancer, glaucoma, and amyotrophic lateral sclerosis (ALS). In cancer, OLFML3’s high expression in tumor tissues makes it a valuable diagnostic marker. Its role in angiogenesis and anoikis resistance also positions it as a promising target for anti-cancer therapies.
In ocular diseases, OLFML3 is associated with glaucoma. Mutations in OLFML3 have been linked to open-angle glaucoma, a condition characterized by impaired drainage of aqueous humor. OLFML3’s expression in ocular tissues and its angiogenic effects suggest its involvement in the pathogenesis of glaucoma.
In ALS, OLFML3 is downregulated in spinal cord tissue, leading to microglial dysfunction. MicroRNA-155, which is upregulated in ALS, targets OLFML3 and suppresses TGFb1/SMAD2 signaling. Restoring OLFML3 expression through miRNA-155 ablation has been shown to improve microglial function and increase survival in ALS models.
Human Tissue Engineering
OLFML3’s role in ECM remodeling and angiogenesis has potential applications in tissue engineering. Electrospun polymer scaffolds combined with OLFML3 have been developed to promote wound healing and tissue regeneration. These scaffolds mimic the native ECM and enhance cell proliferation, neovascularization, and tissue regeneration.
Conclusions
OLFML3 is a multifunctional glycoprotein with significant roles in embryonic development and tumorigenesis. Its unique structure and differential expression patterns distinguish it from other members of the OLF family. OLFML3’s involvement in angiogenesis, anoikis resistance, and EMT highlights its potential as a diagnostic marker and therapeutic target in cancer. Additionally, its roles in CNS development, glaucoma, and ALS underscore its importance in various diseases. Despite the progress made in understanding OLFML3, further research is needed to fully elucidate its biological functions and regulatory mechanisms. Such investigations will pave the way for the development of novel diagnostic and therapeutic strategies.
doi.org/10.1097/CM9.0000000000000309
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