The CCN1 gene, also known as CYR61, is located on chromosome 1 at band 1p22.3. It belongs to the CCN family of proteins, which has six members. CCN1 produces a secreted protein that associates with the extracellular matrix, a network providing structural and biochemical support to cells. This gene’s product acts as a signaling protein, influencing how cells behave and interact within their environment, playing a broad role in various bodily processes.
CCN1’s Essential Contributions to Health
CCN1 plays a role in maintaining health, starting before birth. During embryonic development, it is involved in cardiovascular system formation. It contributes to the development of the heart’s septa. The gene also participates in blood vessel formation within the placenta. A lack of CCN1 in mice can lead to incomplete placental blood vessel networks and compromised embryonic vessels, often resulting in embryonic death. This underscores its role in supporting growth and nutrient exchange during pregnancy.
Beyond embryonic development, CCN1 functions in adult bodily processes, especially inflammation and tissue repair. It coordinates the body’s response to injury, promoting healing across various tissues. For example, in skin wound healing, CCN1 is highly expressed in myofibroblasts.
CCN1 contributes to tissue repair by influencing cell adhesion, migration, and the formation of new blood vessels, known as angiogenesis. It stimulates macrophages to clear apoptotic neutrophils. The gene also regulates extracellular matrix remodeling and can help prevent excessive scarring by inducing senescence in myofibroblasts.
Understanding CCN1’s Diverse Actions and Control
The functions of CCN1 can appear contradictory depending on the cellular environment and cell type. For example, CCN1 can promote cell growth and survival, or trigger programmed cell death (apoptosis) or cellular aging (senescence). This contextual variability means CCN1’s effect is a nuanced response tailored to the cell’s immediate biological needs.
Its actions are mediated by interactions with cellular components, particularly integrin receptors and heparan sulfate proteoglycans. Integrins are cell surface proteins that bridge the cell’s interior and the extracellular matrix, allowing cells to sense and respond to their surroundings. Depending on which specific integrin CCN1 binds to, such as integrin αvβ3 or α6β1, different signaling pathways are activated, leading to distinct cellular outcomes.
For instance, CCN1 can promote cell proliferation, survival, and angiogenesis by binding to integrin αvβ3. Conversely, it can induce apoptosis and senescence when interacting with integrin α6β1 and heparan sulfate proteoglycans. This binding mechanism allows CCN1 to fine-tune its effects, enabling participation in various biological processes, from tissue development and repair to regulating cell fate.
CCN1 expression is under tight control, responding to environmental signals and internal factors. Its production can be increased by growth factors, inflammatory cytokines like IL-1 and TNF-α, and stress stimuli such as low oxygen levels (hypoxia), ultraviolet light, and mechanical stretch. This dynamic regulation ensures CCN1 is produced precisely when and where needed to orchestrate cellular responses.
The Role of CCN1 in Illness
When CCN1’s normal expression or function is disrupted, it can contribute to various diseases. Its altered presence is linked to different forms of cancer, where it can play complex and sometimes opposing roles. In some cancers, such as prostate, ovarian, endometrial, and pancreatic cancers, elevated CCN1 expression can promote tumor growth, migration, and new blood vessel formation. For instance, in aggressive breast cancer cells, CCN1 facilitates migration and protects cells from anoikis, a form of cell death occurring when cells detach from the extracellular matrix.
In lung cancers, including non-small cell lung cancer (NSCLC), CCN1 has been observed to both promote and suppress cancer growth. Researchers are exploring CCN1 modulators as potential cancer therapies to inhibit tumor growth and spread.
CCN1 is also implicated in inflammatory conditions like rheumatoid arthritis (RA). In RA patients, CCN1 is overexpressed in endothelial cells and synovial tissue. It promotes inflammation and contributes to joint damage by inducing inflammatory cytokines like IL-1β and enhancing matrix-degrading enzymes such as MMP-3 in fibroblast-like synoviocytes. CCN1 can also promote monocyte migration and increase angiogenesis in affected joints.
Furthermore, abnormal CCN1 expression is associated with atherosclerosis, a condition where plaque builds up inside arteries. CCN1 is found in atherosclerotic lesions and is induced in endothelial cells by disturbed blood flow. Studies indicate that CCN1 can worsen hyperlipidemia, systemic inflammation, and atherosclerosis progression by impairing cholesterol efflux and downregulating proteins involved in cholesterol clearance. Blocking CCN1’s interaction with integrin α6β1 has been shown to prevent flow-induced changes in endothelial cells and reduce atherosclerosis in mice, suggesting a causative role in the disease.
In diabetes-related kidney disease, known as diabetic nephropathy, CCN1 expression patterns are altered. While typically expressed in podocytes in healthy glomeruli, its expression can decrease in diseased kidneys with severe mesangial expansion. However, in early diabetic nephropathy, increased CCN1 expression has been observed in diabetic mesangial cells and is associated with pro-angiogenic activity, contributing to aberrant angiogenesis.