Biology:Periostin

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

Periostin (POSTN, PN, or osteoblast-specific factor OSF-2) is a protein that in humans is encoded by the POSTN gene. Periostin functions as a ligand for alpha-V/beta-3 and alpha-V/beta-5 integrins to support adhesion and migration of epithelial cells.

Periostin is a gla domain vitamin K dependent factor.

Function

Periostin is a secreted extracellular matrix protein that was originally identified in cells from the mesenchymal lineage (osteoblasts, osteoblast-derived cells, the periodontal ligament, and periosteum). It has been associated with the epithelial-mesenchymal transition in cancer and with the differentiation of mesenchyme in the developing heart. This protein shares a homology with fasciclin I, a secreted cell adhesion molecule found in insects.

In many cancers, periostin binds to integrins on cancer cells, activating the Akt/PKB- and FAK-mediated signaling pathways. This leads to increased cell survival, invasion, angiogenesis, metastasis, and the epithelial-mesenchymal transition.

In humans and mice, periostin undergoes alternative splicing in its C-terminal region, resulting in specific isoforms that can be observed in a broad range of cancers such as pancreatic, colon, and breast cancer.

While periostin plays a wide variety of roles in tissue development along with disease, its function in tissue remodeling as a response to injury is a common underlying role in these different mechanisms. Periostin is transiently upregulated during cell fate changes, whether they are related to alterations in physiology or to pathological changes. It influences extracellular matrix restructuring, tissue remodeling, and the epithelial-mesenchymal transition, all of which can be related to tissue healing, development, and disease. Thus, it functions as a mediator, balancing appropriate and inappropriate responses to tissue damage.

Clinical significance

In valvular heart disease

Periostin plays a critical role in the development of cardiac valves and in degenerative valvular heart disease. While periostin usually is localized to the subendothelial layer in healthy heart valves, its levels are highly increased in infiltrated inflammatory cells and myofibroblasts in angiogenic areas in atherosclerotic and rheumatic valvular heart disease in humans. Periostin has also been shown to increase the secretion of matrix metalloproteinase from valvular intestinal cells, endothelial cells, and macrophages. It is thought that periostin plays a role in cardiac valve complex degeneration by inducing both angiogenesis and matrix metalloproteinase production.

In tissue regeneration and healing

As a matricellular protein, periostin is also important for tissue regeneration. In healthy human skin, periostin is expressed at basal levels and is expressed in the epidermis and hair follicles along with fibronectin and laminin γ2. Periostin is involved in wound healing, helping for the wound to heal faster than when periostin is not present in cells. This delay in wound closure is also associated with a delay in re-epithelialization and a reduction in the proliferation of keratinocytes. Periostin localizes to the extracellular compartment of cells during tissue remodeling associated with wound repair. It may also promote injury closure by facilitating the activation, differentiation, and contraction of fibroblasts. However, the increase in periostin expression associated with tissue regeneration post-injury is transient, starting a few days post-injury, peaking after seven days post-injury, and decreasing afterwards.

In asthma

Periostin is associated with asthma, a fact that is exploited by the experimental asthma medication lebrikizumab.

In cancer

Periostin over-expression was reported in several types of cancer, most frequently in the environment of tumor cells. Recent evidence shows that periostin is a component of the extracellular matrix expressed by fibroblasts in normal tissues and stroma of primary tumor. The metastatic colony formation requires the induction of periostin in the foreign stroma by the infiltrating cancer cells. Periostin production is upregulated in lung fibroblasts by either TGF-β2 or TGF-β3, the latter being secreted by infiltrating cancer stem cells (in MMTV-PyMT mouse breast cancer model)

Periostin has been shown to be highly upregulated in glioblastomas (grade IV gliomas) compared to the normal brain. In gliomas, periostin expression levels correlate directly with tumor grade and recurrence, and inversely with survival. It has been shown that glioma stem cells in glioblastomas secrete periostin, which recruits M2 tumor-associated macrophages from peripheral blood to the tumor environment via αvβ3 integrin signaling. These M2 TAMs differentiate from monocytes once they enter the tumor tissue. Through this recruitment mechanism, periostin supports tumor progression, as M2 tumor-associated macrophages are tumor-supportive and immunosuppressive. In this environment, periostin functions as a chemoattractant, promoting both migration and invasion of macrophages and monocytes into glioblastomas in a dose-dependent manner. Clinically, periostin-associated gene signatures, which are predominated by secreted and matrix proteins, correspond to patient prognosis and malignancy. Given its features related to glioblastoma progression, periostin is a marker of glioma malignancy as well as recurrence of tumors, making it a possible target for therapy that continues to be studied and explored.

Table: Periostin expression in various cancer cell lines.

Cell line	Origin	POSTN/ACTB1
U2OS	Osteosarcoma	3.5±1.7
LB96	Ewing sarcoma	0
LB23-1	Rhabdomyosarcoma	0.1±0.1
HeLa	Cervical cancer	3.0±0.4
PA-1	Ovarian teratocarcinoma	1.4±0.1
LB37-1	NSCLC
LB85	SCLC	3.4±0.2
LB92	SCLC	0.6±0.2
LB1047	Renal cell carcinoma	0.8±0.2
BB64	Renal cell carcinoma	0.08±0.01
LB108	Colorectal cancer	0
MCF7	Breast Cancer	0
Hs578T	Breast Cancer	3693±86
Panc-1	Pancreatic carcinoma	0
Capan-1	Pancreatic carcinoma	0
Huh-7	Hepatocarcinoma	0.3±0.07
LB831	Bladder carcinoma	1748±74
MZGC3	Stomach cancer	0
A172	Glioblastoma	45±4
MZ2	Melanoma	2.3±0.7
LB39	Melanoma	0.5±0.03
LB2586-7	Melanoma	3.4±0.3
LB2201-3	Melanoma	4.2±0.4
A375	Melanoma	4.7±1.2

¹ (cDNA POSTN/cDNA ACTB) × 10⁴

Further reading

• "Serum level of the periostin, a homologue of an insect cell adhesion molecule, as a prognostic marker in nonsmall cell lung carcinomas". Cancer 92 (4): 843–8. Aug 2001. doi:10.1002/1097-0142(20010815)92:4<843::AID-CNCR1391>3.0.CO;2-P. PMID 11550156. 
• "Acquired expression of periostin by human breast cancers promotes tumor angiogenesis through up-regulation of vascular endothelial growth factor receptor 2 expression". Molecular and Cellular Biology 24 (9): 3992–4003. May 2004. doi:10.1128/MCB.24.9.3992-4003.2004. PMID 15082792. 
• "Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt/PKB pathway". Cancer Cell 5 (4): 329–39. Apr 2004. doi:10.1016/S1535-6108(04)00081-9. PMID 15093540. 
• "Periostin is down-regulated in high grade human bladder cancers and suppresses in vitro cell invasiveness and in vivo metastasis of cancer cells". International Journal of Cancer 117 (1): 51–8. Oct 2005. doi:10.1002/ijc.21120. PMID 15880581. 
• "Differential expression of osteoblast-specific factor 2 and polymeric immunoglobulin receptor genes in nasopharyngeal carcinoma". Head & Neck 27 (10): 873–82. Oct 2005. doi:10.1002/hed.20253. PMID 16136586. 
• "Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry". Journal of Proteome Research 4 (6): 2070–80. 2006. doi:10.1021/pr0502065. PMID 16335952. 
• "Transduction of a mesenchyme-specific gene periostin into 293T cells induces cell invasive activity through epithelial-mesenchymal transformation". The Journal of Biological Chemistry 281 (28): 19700–8. Jul 2006. doi:10.1074/jbc.M601856200. PMID 16702213. 
• "Polymorphisms in the KDR and POSTN genes: association with breast cancer susceptibility and prognosis". Breast Cancer Research and Treatment 101 (1): 83–93. Jan 2007. doi:10.1007/s10549-006-9265-1. PMID 16807673. 
• "Establishment of the epithelial-specific transcriptome of normal and malignant human breast cells based on MPSS and array expression data". Breast Cancer Research 8 (5): R56. 2007. doi:10.1186/bcr1604. PMID 17014703. 
• "Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the beta4 integrin and the PI3k pathway". Oncogene 26 (14): 2082–94. Mar 2007. doi:10.1038/sj.onc.1210009. PMID 17043657. 
• "Periostin is frequently overexpressed and enhances invasion and angiogenesis in oral cancer". British Journal of Cancer 95 (10): 1396–403. Nov 2006. doi:10.1038/sj.bjc.6603431. PMID 17060937. 
• "Expression of periostin and its clinicopathological relevance in gastric cancer". World Journal of Gastroenterology 13 (39): 5261–6. Oct 2007. doi:10.3748/wjg.v13.i39.5261. PMID 17876898. 
• "Development of a new ELISA for serum periostin: evaluation of growth-related changes and bisphosphonate treatment in mice". Calcified Tissue International 87 (4): 341–50. Oct 2010. doi:10.1007/s00223-010-9391-y. PMID 20567965. 
• "Overexpression of periostin and lumican in esophageal squamous cell carcinoma". Cancers 2 (1): 133–42. 2010. doi:10.3390/cancers2010133. PMID 24281036.