Periostin Explained

Periostin (POSTN, PN, or osteoblast-specific factor OSF-2) is a protein that in humans is encoded by the POSTN gene.^{[1] [2]} 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.^[3]

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.^[4] 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.^[5]

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.^[4]

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.^[6]

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.^[7]

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.^{[6] [8]} 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.^[8] 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.^[6]

In asthma

Periostin is associated with asthma, a fact that is exploited by the experimental asthma medication lebrikizumab.^[9]

In cancer

Periostin over-expression was reported in several types of cancer, most frequently in the environment of tumor cells.^{[10] [11]} 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) ^[12]

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.^[13] 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.^[14] 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.^[15]

Cell line	Origin	POSTN/ACTB^1
		3.5±1.7
		0
		0.1±0.1
	Cervical cancer	3.0±0.4
	Ovarian teratocarcinoma	1.4±0.1
	NSCLC
	SCLC	3.4±0.2
	SCLC	0.6±0.2
	Renal cell carcinoma	0.8±0.2
	Renal cell carcinoma	0.08±0.01
	Colorectal cancer	0
	Breast Cancer	0
	Breast Cancer	3693±86
	Pancreatic carcinoma	0
	Pancreatic carcinoma	0
		0.3±0.07
	Bladder carcinoma	1748±74
	Stomach cancer	0
		45±4
		2.3±0.7
	Melanoma	0.5±0.03
	Melanoma	3.4±0.3
	Melanoma	4.2±0.4
	Melanoma	4.7±1.2

¹ (cDNA POSTN/cDNA ACTB) × 10⁴

Further reading

• Sasaki H, Dai M, Auclair D, Fukai I, Kiriyama M, Yamakawa Y, Fujii Y, Chen LB . 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 . 11550156 . 10.1002/1097-0142(20010815)92:4<843::AID-CNCR1391>3.0.CO;2-P . free .
• Shao R, Bao S, Bai X, Blanchette C, Anderson RM, Dang T, Gishizky ML, Marks JR, Wang XF . 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 . 15082792 . 387763 . 10.1128/MCB.24.9.3992-4003.2004 .
• Bao S, Ouyang G, Bai X, Huang Z, Ma C, Liu M, Shao R, Anderson RM, Rich JN, Wang XF . 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 . 15093540 . 10.1016/S1535-6108(04)00081-9 . free .
• Kim CJ, Yoshioka N, Tambe Y, Kushima R, Okada Y, Inoue H . 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 . 15880581 . 10.1002/ijc.21120 . free .
• Chang Y, Lee TC, Li JC, Lai TL, Chua HH, Chen CL, Doong SL, Chou CK, Sheen TS, Tsai CH . Differential expression of osteoblast-specific factor 2 and polymeric immunoglobulin receptor genes in nasopharyngeal carcinoma . Head & Neck . 27 . 10 . 873–82 . Oct 2005 . 16136586 . 10.1002/hed.20253 . 25139450 .
• Liu T, Qian WJ, Gritsenko MA, Camp DG, Monroe ME, Moore RJ, Smith RD . Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry . Journal of Proteome Research . 4 . 6 . 2070–80 . 2006 . 16335952 . 1850943 . 10.1021/pr0502065 .
• Yan W, Shao R . 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 . 16702213 . 10.1074/jbc.M601856200 . free .
• Försti A, Jin Q, Altieri A, Johansson R, Wagner K, Enquist K, Grzybowska E, Pamula J, Pekala W, Hallmans G, Lenner P, Hemminki K . 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 . 16807673 . 10.1007/s10549-006-9265-1 . 22086203 .
• Grigoriadis A, Mackay A, Reis-Filho JS, Steele D, Iseli C, Stevenson BJ, Jongeneel CV, Valgeirsson H, Fenwick K, Iravani M, Leao M, Simpson AJ, Strausberg RL, Jat PS, Ashworth A, Neville AM, O'Hare MJ . 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 . 17014703 . 1779497 . 10.1186/bcr1604 . free .
• Baril P, Gangeswaran R, Mahon PC, Caulee K, Kocher HM, Harada T, Zhu M, Kalthoff H, Crnogorac-Jurcevic T, Lemoine NR . 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 . 17043657 . 10.1038/sj.onc.1210009 . 25177405 .
• Siriwardena BS, Kudo Y, Ogawa I, Kitagawa M, Kitajima S, Hatano H, Tilakaratne WM, Miyauchi M, Takata T . Periostin is frequently overexpressed and enhances invasion and angiogenesis in oral cancer . British Journal of Cancer . 95 . 10 . 1396–403 . Nov 2006 . 17060937 . 2360586 . 10.1038/sj.bjc.6603431 .
• Li JS, Sun GW, Wei XY, Tang WH . Expression of periostin and its clinicopathological relevance in gastric cancer . World Journal of Gastroenterology . 13 . 39 . 5261–6 . Oct 2007 . 17876898 . 4171309 . 10.3748/wjg.v13.i39.5261 . free .
• Contié S, Voorzanger-Rousselot N, Litvin J, Bonnet N, Ferrari S, Clézardin P, Garnero P . 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 . 20567965 . 10.1007/s00223-010-9391-y . 22592909 .
• Kashyap MK, Marimuthu A, Peri S, Kumar GS, Jacob HK, Prasad TS, Mahmood R, Kumar KV, Kumar MV, Meltzer SJ, Montgomery EA, Kumar RV, Pandey A . Overexpression of periostin and lumican in esophageal squamous cell carcinoma . Cancers . 2 . 1 . 133–42 . 2010 . 24281036 . 10.3390/cancers2010133 . 3827595. free .

Notes and References

1. Takeshita S, Kikuno R, Tezuka K, Amann E . Osteoblast-specific factor 2: cloning of a putative bone adhesion protein with homology with the insect protein fasciclin I . The Biochemical Journal . 294 . 1. 271–8 . Aug 1993 . 8363580 . 1134594 . 10.1042/bj2940271. 294 .
2. Web site: Entrez Gene: POSTN periostin, osteoblast specific factor.
3. Coutu DL, Wu JH, Monette A, Rivard GE, Blostein MD, Galipeau J . Periostin, a member of a novel family of vitamin K-dependent proteins, is expressed by mesenchymal stromal cells . The Journal of Biological Chemistry . 283 . 26 . 17991–8001 . Jun 2008 . 18450759 . 10.1074/jbc.M708029200 . free .
4. Hoersch S, Andrade-Navarro MA . Periostin shows increased evolutionary plasticity in its alternatively spliced region . BMC Evolutionary Biology . 10 . 30 . 20109226 . 10.1186/1471-2148-10-30 . 2010 . 1 . 2824660 . free . 2010BMCEE..10...30H .
5. Morra L, Moch H . Periostin expression and epithelial-mesenchymal transition in cancer: a review and an update . Virchows Archiv . 459 . 5 . 465–75 . Nov 2011 . 21997759 . 10.1007/s00428-011-1151-5 . 3205268.
6. Conway SJ, Izuhara K, Kudo Y, Litvin J, Markwald R, Ouyang G, Arron JR, Holweg CT, Kudo A . The role of periostin in tissue remodeling across health and disease . Cellular and Molecular Life Sciences . 71 . 7 . 1279–88 . Apr 2014 . 24146092 . 10.1007/s00018-013-1494-y . 3949008.
7. Hakuno D, Kimura N, Yoshioka M, Mukai M, Kimura T, Okada Y, Yozu R, Shukunami C, Hiraki Y, Kudo A, Ogawa S, Fukuda K . Periostin advances atherosclerotic and rheumatic cardiac valve degeneration by inducing angiogenesis and MMP production in humans and rodents . The Journal of Clinical Investigation . 120 . 7 . 2292–306 . Jul 2010 . 20551517 . 10.1172/JCI40973 . 2898587.
8. Braun N, Sen K, Alscher MD, Fritz P, Kimmel M, Morelle J, Goffin E, Jörres A, Wüthrich RP, Cohen CD, Segerer S . Periostin: a matricellular protein involved in peritoneal injury during peritoneal dialysis . Peritoneal Dialysis International . 33 . 5 . 515–28 . 23378472 . 10.3747/pdi.2010.00259 . 3797670. 2013 .
9. Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, Harris JM, Scheerens H, Wu LC, Su Z, Mosesova S, Eisner MD, Bohen SP, Matthews JG . Lebrikizumab treatment in adults with asthma . The New England Journal of Medicine . 365 . 12 . 1088–98 . Sep 2011 . 21812663 . 10.1056/NEJMoa1106469 . free .
10. Gillan L, Matei D, Fishman DA, Gerbin CS, Karlan BY, Chang DD . Periostin secreted by epithelial ovarian carcinoma is a ligand for alpha(V)beta(3) and alpha(V)beta(5) integrins and promotes cell motility . Cancer Research . 62 . 18 . 5358–64 . Sep 2002 . 12235007 .
11. Contié S, Voorzanger-Rousselot N, Litvin J, Clézardin P, Garnero P . Increased expression and serum levels of the stromal cell-secreted protein periostin in breast cancer bone metastases . International Journal of Cancer . 128 . 2 . 352–60 . Jan 2011 . 20715172 . 10.1002/ijc.25591 . 37866040 . free .
12. Malanchi I, Santamaria-Martínez A, Susanto E, Peng H, Lehr HA, Delaloye JF, Huelsken J . Interactions between cancer stem cells and their niche govern metastatic colonization . Nature . 481 . 7379 . 85–9 . Jan 2012 . 22158103 . 10.1038/nature10694 . 2012Natur.481...85M . 2128276 . 2297/35864 . free .
13. Mikheev AM, Mikheeva SA, Trister AD, Tokita MJ, Emerson SN, Parada CA, Born DE, Carnemolla B, Frankel S, Kim DH, Oxford RG, Kosai Y, Tozer-Fink KR, Manning TC, Silber JR, Rostomily RC . Periostin is a novel therapeutic target that predicts and regulates glioma malignancy . Neuro-Oncology . Aug 2014 . 25140038 . 10.1093/neuonc/nou161 . 17 . 3 . 372–82 . 4483094.
14. Zhou W, Ke SQ, Huang Z, Flavahan W, Fang X, Paul J, Wu L, Sloan AE, McLendon RE, Li X, Rich JN, Bao S . Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth . Nature Cell Biology . 17 . 2 . 170–82 . Feb 2015 . 25580734 . 10.1038/ncb3090 . 4312504.
15. Tilman G, Mattiussi M, Brasseur F, van Baren N, Decottignies A . Human periostin gene expression in normal tissues, tumors and melanoma: evidences for periostin production by both stromal and melanoma cells . Molecular Cancer . 6 . 80 . 80 . 2007 . 18086302 . 2222651 . 10.1186/1476-4598-6-80 . free .