Osteopontin (Spp1)
Synonyms
Bone sialoprotein 1; BNSP; BSPI; Early T-lymphocyte activation 1; ETA-1; Nephropontin; OPN; Osteopontin; Osteopontin-C; Osteopontin-D; Osteopontin/immunoglobulin alpha 1 heavy chain constant region fusion protein; PSEC0156; SPP-1; Secreted phosphoprotein 1; Secreted phosphoprotein 1 (osteopontin, bone sialoprotein I, early T-lymphocyte activation 1); SPP1; SPP1/CALPHA1 fusion; Urinary stone protein; Uropontin
Historical Background
The protein product of gene Spp1 is known by many names; however, osteopontin (OPN) is the most widely used and preferred. Osteopontin was first identified in osteoblasts and is primarily known for its role in bone mineralization, hence derives the name “osteo” for bone and pontin from “pons”- bridge in Latin. Orthologous gene analysis of Spp1 gene indicates that it is found in 39 eukaryotic genera. In humans, OPN is expressed in many organs and plays an important role in many cellular, physiological, immunological, and pathological processes; thus, OPN is a multifunctional protein. It belongs to one of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family of secreted phosphoproteins; other proteins in this family include integrin-binding sialoprotein (IBSP), dentin matrix protein 1 (DMP1), dentin sialophosphoprotein (DSPP), and matrix extracellular phosphoglycoprotein (MEPE). OPN was first described by Donald Senger, of Massachusetts Institute of Technology (Senger et al. 1980), and then by many other groups (Prince et al. 1987; Oldberg et al. 1986). The protein was first characterized for glycosylation by Franzén and Heinegård (Franzen and Heinegard 1985). However, the role of OPN in cancer was first proposed by Smith and Denhardt in 1987 (Smith and Denhardt 1987). This chapter will give a brief overview of OPN and its significance in cancer.
Gene Location
Position of Spp1 gene on chromosome 4 flanked by HSP90AB3P and PDK2 genes
Structure
Nascent OPN is 300–314 amino acid long and approximately 33 kDa protein; however, after glycosylation the molecular weight ranges from 44–75 kDa. The protein is comprised of negatively charged, hydrophilic amino acids such as Asp and Glu. OPN contains a signal peptide for translocating the translated protein into the endoplasmic reticulum for posttranslational modification. The protein undergoes phosphorylation, sulfation, and glycosylation. The type and amount of posttranslational modification depend on the cell type and thus perform different function (Sodek et al. 2000). Therefore, the molecular weight varies from species to species and cell types to cell types. The protein FAM20C phosphorylates OPN at multiple sites within the S-x-E/pS motif in the extracellular medium. N- and O-glycosylation are carried out at by glycosyltransferases at Asp and Ser/Thr, respectively. OPN is then secreted out of the cell where it is known as sOPN; however, not all OPN is secreted; the intracellular OPN (iOPN) is found in cytoplasm and nucleus (Inoue and Shinohara 2011). (This chapter addresses sOPN as OPN.)
Protein sequence alignment of human and mouse OPN and various domains show 63% sequence similarity (http://www.ebi.ac.uk/Tools/msa/muscle/) (MMP – matrix metalloproteinases)
Network shows different interaction of Spp1 gene product OPN with other proteins. The interactions are derived and modified from STRING v10 (http://string-db.org), which shows OPN mainly interacting with integrin (ITGA/B), CD44, PTK2B protein tyrosine kinase 2 beta, as well as thrombospondin
The top five three-dimensional structures predicted for OPN using I-TASSER (http://zhanglab.ccmb.med.umich.edu/I-TASSER/). The nature of OPN as intrinsically disordered protein is demonstrated by the variation in the structures (a–e); therefore, there is no curated structure for OPN. The α-helix and β-sheets are represented in red and blue color, respectively
Regulation
The regulation of OPN is influenced by many factors and is not very well understood. It is observed that OPN is upregulated by many activators such as EGF, hepatocyte growth factor, platelet-derived growth factor, parathyroid hormone, nitric oxide, TNF-α, IL-1β, angiotensin II, TGF-β, hyperglycemia, and hypoxia (Mazzali et al. 2002). It is not exactly clear how OPN is regulated; however, the Spp1 gene promoter elements may help to understand. The promoter driving Spp1 gene contains TATA-like, CAAT-like motifs along with RE-1 element. The RE-1 element consists of RE-1a (−55 to −86) which harbors binding sites for transcription factors Sp1, glucocorticoid receptor, and the E-box-binding factors; and RE-1b (−22 to −45) contains octamer motif-binding protein (OCT-1/OCT-2). It was also observed that myc binds to RE-1a and OCT-1 binds RE-1b and these elements work synergistically (Wang et al. 2000). However, the promoter also shows presence of Ras-activated enhancer sequence, vitamin D responsive element, and interferon-inducible element (Mazzali et al. 2002). In addition to these regulators, miRNAs have also been identified to target OPN expression. Our lab and others have shown that hsa-miR-299-5p, hsa-miR-335-5p, and hsa-miR-146a-5p target human OPN expression (http://mirtarbase.mbc.nctu.edu.tw/index.php).
Function
Schematic shows that OPN regulates different cellular processes that are directly or indirectly associated with cancer
The levels of OPN expressed in normal and cancer organs modified from the data CAB002212 at the protein atlas (http://www.proteinatlas.org/)
Organs expressing OPN | Level of OPN expressed | |
---|---|---|
Normal | Cancer | |
Brain | Not detected | High, medium |
Breast | Low | High, medium |
Cervix | Not detected | High, medium, low |
Colon/rectum | Medium | High, medium, low |
Endometrium | Low | High, medium, low |
Head and neck | Low | Medium, low |
Kidney | High | High, medium, low |
Liver | Not detected | High, medium, low |
Lungs | Medium | Medium, low |
Lymph node | Low | Medium, low |
Ovary | Not available | High, medium, low |
Pancreas | Medium | High, medium, low |
Prostate | Not detected | High, medium, low |
Skin | Not detected | High, medium, low |
Stomach | Low | High, medium |
Testis | Not detected | High, medium, low |
Urinary bladder | Low | High, medium, low |
Different mutations found in Spp1 gene from the cancer specimens are transformed and represented on the OPN amino acid positions (Obtained from cBioPortal for Cancer Genomics (http://www.cbioportal.org/)). The green knobs represent missense mutation while, the red knobs represent truncated mutations
Cell adhesion: OPN promotes cell adhesion by interacting with integrins present on the cell surface through the RGD-dependent mechanism (Liaw et al. 1994). However, OPN is also known to help adhesion without the RGD by not interacting with alpha v integrin (Katagiri et al. 1996). Another interesting aspect is that the balance of glycosylation and phosphorylation determines the function of OPN in cell adhesion. The O-glycosylation of OPN determines the level of phosphorylation and modulates cell adhesion. O-glycosylation suppresses phosphorylation which reduces cell adhesion (Kariya et al. 2014). The thrombin cleavage sites on OPN are important for cell adhesion as the deletion of cleavage sites or inhibition of thrombin resulted in decreased cell adhesion (Beausoleil et al. 2011; Schulze et al. 2008). This has implication on establishment of metastatic cell at other organ or sites in the body.
Epithelial-mesenchymal transition (EMT): The transition of epithelial to mesenchymal phenotype or vice versa is required for developmental processes, wound healing, and the maintenance of structural integrity (Kalluri and Weinberg 2009). However, EMT is the characteristic of cancer development. The dysfunction in these transition events leads to cancer progression and is commonly observed in the bladder, brain, breast, cervical, colon/rectum, liver, lungs, ovarian, prostate, pancreas, renal, and skin (Heerboth et al. 2015). OPN regulation of EMT was demonstrated in a mouse xenograft model (Bhattacharya et al. 2012). It was also noted that the up-regulation of OPN promotes EMT in breast, colorectal, gastric, liver and ovarian cancer. OPN mediates EMT downstream (downstream of what?) with transcription factors such as TWIST, ZEB, and SNAIL (Kothari et al. 2016). In cancer, EMT is the interplay of HF-1 α, PI3K/AKT, and NF-κB pathways mediated or initiated by OPN.
Metastasis: As OPN facilitates EMT, this eventually leads to metastasis; the general prerequisite for metastasis is through the mesenchymal phenotype. It starts with increased motility and invasiveness and the migrated cells establish (cell adhesion) and form a tumor (angiogenesis) on the site, by virtue of OPN (Larue and Bellacosa 2005). The isoforms of OPN are an important part of this process. Metastasis increases in the cells expressing OPN and the inhibition of OPN reverses it. In cases of non-small lung cancer, metastasis from the lungs was reduced when OPN was neutralized with a monoclonal antibody (Shojaei et al. 2012). Hepatic metastasis in colorectal cancer was associated with OPN due to decreased homotypic adhesion and increased heterotypic adhesion (Kyprianou et al. 2012). Similarly, OPN has been established as a key player in the metastasis from breast cancer and lungs and bone metastasis is established (Ibrahim et al. 2000).
Role in immunity: OPN is a secretory cytokine and plays an active role in inflammation at the systemic or local cancer microenvironment. External injection of OPN recruits macrophages and T-cells at the site demonstrating its chemotactic function. OPN also increases the cell adhesion of these cells, and if the gene Spp1 is silenced or OPN is neutralized with antibodies, the cells adhesion is reduced. The recruitment of leucocytes creates a pro-inflammatory environment around and supports Th1 and suppresses Th2 immune response (Mazzali et al. 2002). OPN stimulates IL-12 production and suppression of IL-10 as a pro-inflammatory cytokine; however, it is also known to be anti-inflammatory. Under stress or inflammation, the enzyme nitric oxide synthase (iNOS) produces nitric oxide (NO) in the cells, and this NO induces OPN to inhibit iNOS. A feedback inhibition of iNOS is regulated by OPN and thus acts as anti-inflammatory (Denhardt et al. 2001). The pro- and anti-inflammatory feature of OPN makes it ideal for cancer progression. A balanced inflammatory microenvironment is important for cancer, as limited inflammation restricts tumor growth, while excess inflammation causes tumor regression (Coussens and Werb 2002). It is interesting to know that OPN produced by tumors or a host acts as an immunosuppressor in the metastatic microenvironment probably due to the regulation of inflammation and favorable cancer growth (Sangaletti et al. 2014). In the tumor microenvironment, OPN offers this strategy of self-survival and proliferation for the tumor mass (or cancer cell population), in addition to favoring angiogenesis, resisting apoptosis.
Drug resistance: The anticancer drugs are effective in targeting cancer cells; however, the chemotherapy regime faces difficulties due the drug resistance. The mutations in cancer may increase the transporter activity or degrade the drug to reduce the intracellular concentration of drug. Alternate mechanism involves mutation in target protein or epigenetic modification, alteration in DNA repair, or cell cycle processes (Florea and Büsselberg 2013). OPN is one of the proteins that is responsible for drug resistance as an effect of the aforementioned processes. OPN leads to up-regulation of the ABCB1 and ABCG2 transporters that causes drug resistance. Conversely, silencing of Spp1 gene leads to sensitivity to actinomycin-D, cyclophosphamide, doxorubicin, paclitaxel, and rapamycin (Shevde and Samant 2014). Knockout of Spp1 in MDA-MB-231 shows that sensitivity to doxorubicin and radiobiologicals is increased. Similarly, overproduction of OPN increases resistance to oxaliplatin in colorectal cancer (Ng et al. 2015) and cisplatin in oral squamous cell carcinoma (Luo et al. 2015). Elevated levels of OPN in cancer patients are also linked with poor prognosis. Thus, it is very clear that drug resistance and OPN are positively correlated.
Targeting Osteopontin
Direct or indirect inhibitors of OPN have potential for therapeutics. Aptamers are DNA, RNA, or peptide that form complex three-dimensional structure to occupy an active site or bind to target protein resulting in its inactivation. These molecules hold promise for cancer therapeutics and the list against the cancer targets are increasing day by day (Sun et al. 2014). OPN-R3 aptamers that directly inhibit OPN have been developed, and its administration has reversed breast cancer growth and reduced metastasis (Mi et al. 2008; Talbot et al. 2011). Similar results were observed when Spp1 gene transcripts were silenced using siRNA and shRNA (Shevde and Samant 2014). Also, an antibody against OPN was able to reduce the metastasis significantly in non-small lung cancer (Shojaei et al. 2012). Currently there are very few known inhibitors of OPN. However, agelastatin A alkaloid is 1.5–16 times more potent than cisplatin and is found in the sponge Agelas dendromorpha. Agelastatin A has been beneficial in bladder, breast, colon, and skin cancer. This alkaloid stalls the cancerous cells in the G2 phase of the cell cycle by downregulating β-catenin while upregulating the cellular Tcf-4 that inhibits OPN (Mason et al. 2008). Similarly, another indirect way of targeting OPN is by argatroban, a thrombin inhibitor. The activity of OPN is enhanced by the cleavage of OPN at thrombin sites by thrombin; however, this can be hindered by argatroban (Schulze et al. 2008). These therapeutics need thorough investigation of the short- and long-term consequences in normal physiology, as abnormal morphogenesis and lactation deficiencies have been reported in mammary glands due the inhibition of OPN (Nemir et al. 2000).
Summary
Besides the normal function of OPN in bone modeling, it is clear that it is one of the important players in cancer. The role of OPN is important for understanding the complexity and diversity of cancer. Currently, the snapshots of OPN’s operation and its ability to modulate inflammation, cell proliferation, apoptosis, metastasis, and drug resistance are known. However, the utilization of this knowledge to target this influential molecule has not been achieved yet. The challenges for the development of drugs targeting OPN are due to IDP nature and unclear implication of impairing OPN function. On the other hand, OPN can be used as a significant cancer diagnostic marker (along with other markers) to distinguish OPN associated with normal and cancer in the clinical setup.
Notes
Acknowledgments
NIH R01CA194048 grant to R.S.S.
References
- Anborgh PH, Mutrie JC, Tuck AB, Chambers AF. Pre- and post-translational regulation of osteopontin in cancer. J of Cell Commun Signal. 2011;5:111–22. doi:10.1007/s12079-011-0130-6.CrossRefGoogle Scholar
- Beausoleil MS, Schulze EB, Goodale D, Postenka CO, Allan AL. Deletion of the thrombin cleavage domain of osteopontin mediates breast cancer cell adhesion, proteolytic activity, tumorgenicity, and metastasis. BMC Cancer. 2011;11. doi:10.1186/1471-2407-11-25.Google Scholar
- Bhattacharya SD, Mi Z, Kim VM, Guo H, Talbot LJ, Kuo PC. Osteopontin regulates epithelial mesenchymal transition-associated growth of hepatocellular cancer in a mouse xenograft model. Ann Surg. 2012;255:319–25. doi:10.1097/SLA.0b013e31823e3a1c.PubMedPubMedCentralCrossRefGoogle Scholar
- Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7. doi:10.1038/nature01322.PubMedPubMedCentralCrossRefGoogle Scholar
- Das S, Samant RS, Shevde LA. Nonclassical activation of Hedgehog signaling enhances multidrug resistance and makes cancer cells refractory to smoothened-targeting Hedgehog inhibition. J Biol Chem. 2013;288:11824–33. doi:10.1074/jbc.M112.432302.PubMedPubMedCentralCrossRefGoogle Scholar
- Denhardt DT, Noda M, O’Regan AW, Pavlin D, Berman JS. Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. J Clin Investig. 2001;107:1055–61. doi:10.1172/jci12980.PubMedPubMedCentralCrossRefGoogle Scholar
- Fisher LW. DMP1 and DSPP: evidence for duplication and convergent evolution of two SIBLING proteins. Cells Tissues Organs. 2011;194:113–8. doi:10.1159/000324254.PubMedPubMedCentralCrossRefGoogle Scholar
- Florea A-M, Büsselberg D. Breast cancer and possible mechanisms of therapy resistance. J Local Global Health. 2013;2. doi:10.5339/jlghs.2013.2.Google Scholar
- Franzen A, Heinegard D. Isolation and characterization of two sialoproteins present only in bone calcified matrix. Biochem J. 1985;232:715–24.PubMedPubMedCentralCrossRefGoogle Scholar
- Heerboth S, Housman G, Leary M, Longacre M, Byler S, Lapinska K, et al. EMT and tumor metastasis. Clin Transl Med. 2015;4. doi:10.1186/s40169-015-0048-3.Google Scholar
- Ibrahim T, Leong I, Sanchez-Sweatman O, Khokha R, Sodek J, Tenenbaum HC, et al. Expression of bone sialoprotein and osteopontin in breast cancer bone metastases. Clin Exp Metastasis. 2000;18:253–60.PubMedCrossRefGoogle Scholar
- Inoue M, Shinohara ML. Intracellular osteopontin (iOPN) and immunity. Immunol Res. 2011;49:160–72. doi:10.1007/s12026-010-8179-5.PubMedPubMedCentralCrossRefGoogle Scholar
- Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Investig. 2009;119:1420–8. doi:10.1172/jci39104.PubMedPubMedCentralCrossRefGoogle Scholar
- Kariya Y, Kanno M, Matsumoto-Morita K, Konno M, Yamaguchi Y, Hashimoto Y. OsteopontinO-glycosylation contributes to its phosphorylation and cell-adhesion properties. Biochem J. 2014;463:93–102. doi:10.1042/bj20140060.PubMedCrossRefGoogle Scholar
- Katagiri YU, Murakami M, Mori K, Iizuka J, Hara T, Tanaka K, et al. Non-RGD domains of osteopontin promote cell adhesion without involving alpha v integrins. J Cell Biochem. 1996;62:123–31. doi:10.1002/(SICI)1097-4644(199607)62:1<123::AID-JCB13>3.0.CO;2-O.PubMedCrossRefGoogle Scholar
- Kothari A, Arffa M, Chang V, Blackwell R, Syn W-K, Zhang J, et al. Osteopontin – a master regulator of epithelial-mesenchymal transition. J Clin Med. 2016;5:39. doi:10.3390/jcm5040039.PubMedCentralCrossRefGoogle Scholar
- Kurzbach D, Platzer G, Schwarz TC, Henen MA, Konrat R, Hinderberger D. Cooperative unfolding of compact conformations of the intrinsically disordered protein osteopontin. Biochemistry. 2013;52:5167–75. doi:10.1021/bi400502c.PubMedPubMedCentralCrossRefGoogle Scholar
- Kyprianou N, Huang J, Pan C, Hu H, Zheng S, Ding L. Osteopontin-enhanced hepatic metastasis of colorectal cancer cells. PLoS One. 2012;7:e47901. doi:10.1371/journal.pone.0047901.CrossRefGoogle Scholar
- Larue L, Bellacosa A. Epithelial–mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene. 2005;24:7443–54. doi:10.1038/sj.onc.1209091.PubMedCrossRefGoogle Scholar
- Liaw L, Almeida M, Hart CE, Schwartz SM, Giachelli CM. Osteopontin promotes vascular cell adhesion and spreading and is chemotactic for smooth muscle cells in vitro. Circ Res. 1994;74:214–24.PubMedCrossRefGoogle Scholar
- Luo S-D, Chen Y-J, Liu C-T, Rau K-M, Chen Y-C, Tsai H-T, et al. Osteopontin involves cisplatin resistance and poor prognosis in oral squamous cell carcinoma. Biomed Res Int. 2015;2015:1–13. doi:10.1155/2015/508587.Google Scholar
- Machado JP, Johnson WE, O’Brien SJ, Vasconcelos V, Antunes A. Adaptive evolution of the matrix extracellular phosphoglycoprotein in mammals. BMC Evol Biol. 2011;11:342. doi:10.1186/1471-2148-11-342.PubMedPubMedCentralCrossRefGoogle Scholar
- Mason CK, McFarlane S, Johnston PG, Crowe P, Erwin PJ, Domostoj MM, et al. Agelastatin A: a novel inhibitor of osteopontin-mediated adhesion, invasion, and colony formation. Mol Cancer Ther. 2008;7:548–58. doi:10.1158/1535-7163.mct-07-2251.PubMedCrossRefGoogle Scholar
- Mazzali M, Kipari T, Ophascharoensuk V, Wesson JA, Johnson R, Hughes J. Osteopontin – a molecule for all seasons. QJM: Mon J Assoc Physicians. 2002;95:3–13.CrossRefGoogle Scholar
- Mi Z, Guo H, Russell MB, Liu Y, Sullenger BA, Kuo PC. RNA aptamer blockade of osteopontin inhibits growth and metastasis of MDA-MB231 breast cancer cells. Mol Ther. 2008;17:153–61. doi:10.1038/mt.2008.235.PubMedPubMedCentralCrossRefGoogle Scholar
- Mi Z, Guo H, Kuo PC. Identification of osteopontin-dependent signaling pathways in a mouse model of human breast cancer. BMC Res Notes. 2009;2:119. doi:10.1186/1756-0500-2-119.PubMedPubMedCentralCrossRefGoogle Scholar
- Mitra A, Menezes ME, Pannell LK, Mulekar MS, Honkanen RE, Shevde LA, et al. DNAJB6 chaperones PP2A mediated dephosphorylation of GSK3beta to downregulate beta-catenin transcription target, osteopontin. Oncogene. 2012;31:4472–83. doi:10.1038/onc.2011.623.PubMedPubMedCentralCrossRefGoogle Scholar
- Nemir M, Bhattacharyya D, Li X, Singh K, Mukherjee AB, Mukherjee BB. Targeted inhibition of osteopontin expression in the mammary gland causes abnormal morphogenesis and lactation deficiency. J Biol Chem. 2000;275:969–76.PubMedCrossRefGoogle Scholar
- Ng L, Wan T, Chow A, Iyer D, Man J, Chen G, et al. Osteopontin overexpression induced tumor progression and chemoresistance to oxaliplatin through induction of stem-like properties in human colorectal cancer. Stem Cells Int. 2015;2015:1–8. doi:10.1155/2015/247892.CrossRefGoogle Scholar
- Oldberg A, Franzen A, Heinegard D. Cloning and sequence analysis of rat bone sialoprotein (osteopontin) cDNA reveals an Arg-Gly-Asp cell-binding sequence. Proc Natl Acad Sci U S A. 1986;83:8819–23.PubMedPubMedCentralCrossRefGoogle Scholar
- Prince CW, Oosawa T, Butler WT, Tomana M, Bhown AS, Bhown M, et al. Isolation, characterization, and biosynthesis of a phosphorylated glycoprotein from rat bone. J Biol Chem. 1987;262:2900–7.PubMedGoogle Scholar
- Sangaletti S, Tripodo C, Sandri S, Torselli I, Vitali C, Ratti C, et al. Osteopontin shapes immunosuppression in the metastatic Niche. Cancer Res. 2014;74:4706–19. doi:10.1158/0008-5472.can-13-3334.PubMedCrossRefGoogle Scholar
- Schulze EB, Hedley BD, Goodale D, Postenka CO, Al-Katib W, Tuck AB, et al. The thrombin inhibitor Argatroban reduces breast cancer malignancy and metastasis via osteopontin-dependent and osteopontin-independent mechanisms. Breast Cancer Res Treat. 2008;112:243–54. doi:10.1007/s10549-007-9865-4.PubMedCrossRefGoogle Scholar
- Senger DR, Wirth DF, Hynes RO. Transformation-specific secreted phosophoproteins. Nature. 1980;286:619–21.PubMedCrossRefGoogle Scholar
- Shevde LA, Samant RS. Role of osteopontin in the pathophysiology of cancer. Matrix Biol. 2014;37:131–41. doi:10.1016/j.matbio.2014.03.001.PubMedCrossRefGoogle Scholar
- Shojaei F, Scott N, Kang X, Lappin PB, Fitzgerald AA, Karlicek S, et al. Osteopontin induces growth of metastatic tumors in a preclinical model of non-small lung cancer. J Exp Clin Cancer Res. 2012;31:26. doi:10.1186/1756-9966-31-26.PubMedPubMedCentralCrossRefGoogle Scholar
- Smith JH, Denhardt DT. Molecular cloning of a tumor promoter-inducible mRNA found in JB6 mouse epidermal cells: induction is stable at high, but not at low, cell densities. J Cell Biochem. 1987;34:13–22. doi:10.1002/jcb.240340103.PubMedCrossRefGoogle Scholar
- Sodek J, Ganss B, McKee MD. Osteopontin. Crit Rev Oral Biol Med: An Off Publ Am Assoc Oral Biologists. 2000;11:279–303.CrossRefGoogle Scholar
- Sun H, Zhu X, Lu PY, Rosato RR, Tan W, Zu Y. Oligonucleotide aptamers: new tools for targeted cancer therapy. Mol Ther: Nucleic Acids. 2014;3:e182. doi:10.1038/mtna.2014.32.PubMedPubMedCentralGoogle Scholar
- Talbot LJ, Mi Z, Bhattacharya SD, Kim V, Guo H, Kuo PC. Pharmacokinetic characterization of an RNA aptamer against osteopontin and demonstration of in vivo efficacy in reversing growth of human breast cancer cells. Surgery. 2011;150:224–30. doi:10.1016/j.surg.2011.05.015.PubMedPubMedCentralCrossRefGoogle Scholar
- Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347:1260419. doi:10.1126/science.1260419.PubMedCrossRefGoogle Scholar
- Wang D, Yamamoto S, Hijiya N, Benveniste EN, Gladson CL. Transcriptional regulation of the human osteopontin promoter: functional analysis and DNA-protein interactions. Oncogene. 2000;19:5801–9. doi:10.1038/sj.onc.1203917.PubMedCrossRefGoogle Scholar
- Weber GF. The cancer biomarker osteopontin: combination with other markers. Cancer Genomics Proteomics. 2011;8:263–88.PubMedGoogle Scholar