|Year : 2015 | Volume
| Issue : 4 | Page : 88-93
|Understanding oral cancer at molecular level: The new frontier
Kavita Manchanda1, Avishek De Sarkar2, Isha Chauhan3, Neha Sharma4, Shailee Fotedar1, Vikas Fotedar5
1 Department of Public Health Dentistry, Government Dental College and Hospital, Shimla, Himachal Pradesh, India
2 Department of Oral and Maxillofacial Surgery, Gurunanak Institute of Dental Science Research, Kolkata, West Bengal, India
3 Department of Oral Pathology and Microbiology, Government Dental College and Hospital, Shimla, Himachal Pradesh, India
4 Department of Conservative and Endodontic, Government Dental College and Hospital, Shimla, Himachal Pradesh, India
5 Department of Radiation Oncology, Regional Cancer Centre, IGMC, Shimla, Himachal Pradesh, India
Click here for correspondence address and email
|Date of Web Publication||7-Aug-2015|
| Abstract|| |
Oral cancer is one of the major threats to public health in developed as well as developing countries. Despite the current therapeutic modalities, which include the use of nonselective treatments (surgery, radiation, and chemotherapy), the mortality and morbidity rates still remain high due to delays in diagnosis and treatment. Thus, it is important to completely understand the molecular mechanism in the development of oral cancer to further develop more selective treatment. This review attempts to identify and understand the deregulated molecular pathways and related genes in oral carcinogenesis.
Keywords: Cancer, genetics, hallmarks, molecular biology, oral cancer, squamous cell carcinoma (SCC)
|How to cite this article:|
Manchanda K, Sarkar AD, Chauhan I, Sharma N, Fotedar S, Fotedar V. Understanding oral cancer at molecular level: The new frontier. Ann Trop Med Public Health 2015;8:88-93
|How to cite this URL:|
Manchanda K, Sarkar AD, Chauhan I, Sharma N, Fotedar S, Fotedar V. Understanding oral cancer at molecular level: The new frontier. Ann Trop Med Public Health [serial online] 2015 [cited 2020 May 28];8:88-93. Available from: http://www.atmph.org/text.asp?2015/8/4/88/162314
| Introduction|| |
Oral and pharyngeal cancer, grouped together, is the sixth-most common cancer in the world.  Although there has been a reduction in total mortality over the past two decades, the 5-year relative cancer survival rate for oral cancer is one of the lowest, far below the rate for many other cancers, including skin melanoma and cancers of the testis, breast, colon, rectum, and kidney. 
Oral squamous cell carcinoma (OSCC) is among the most frequently seen of all oral cancers.  Tobacco and alcohol remain the most important risk factors for squamous cell carcinomas (SCCs) of the oral cavity,  but a genetic predisposition has also been suggested, due to the fact that the majority of the population exposed to these risk factors do not develop oral cancer and the fact that sporadic cases of oral tumors occur in young adults and nonusers of tobacco and alcohol.  Oral cancers are characterized by a multitude of these genetic alterations  and have a remarkable incidence with fairly poor prognosis, which has encouraged the setting up of many studies to explore the underlying mechanism of its development.  In the following review, we address the information currently available for several genetic and molecular aspects of oral cancer and the metastatic process, as it will help in recognizing the population at risk and in enabling prompt treatment due to early diagnosis.
| Basic Concept of Tumor Biology|| |
Clonal evolution 
The dominant theory of tumor development over the past 30 years has been the clonal evolution theory, first proposed in 1976 by Nowell. In this model, repeated carcinogenic insults, or "events," occur within a cell, usually at the genetic or epigenetic level. When enough events occur, a selective growth advantage is conferred on the affected cell. As this cell proliferates, mutant progeny arise as a result of further insults and genomic instability. Most of the offspring do not survive because of immunologic surveillance, apoptosis, or metabolic derangement. Eventually, however, a dominant clonal population of cells is produced that not only survives, but flourishes. As evolution occurs within this clonal population, new clones are produced with acquired additional characteristics, such as the capacity for invasion, that define cancer.
Molecular progression model 
Over the past 20 years, investigators have identified a number of acquired alterations in oncogenes and tumor suppressor genes and have tried to coordinate these genotypic changes with the phenotypic changes seen clinically. Initial work by van der Riet et al. has assembled these genetic events, whether they result from cytogenetic alterations, interaction with viral products, or damage from radiation or chemical carcinogens, into an "allelotype" for head and neck carcinoma. This has led to the development of a molecular progression model for head and neck cancer. Again, it is the accumulation of genetic events and not the specific ordering of the events that appears to be associated with phenotypic progression. This model is important not only for understanding the pathogenesis of head and neck cancer, but also for developing new diagnostic, staging, and therapeutic techniques.
Field carcinogenesis 
Clear evidence exists that exposure to the carcinogens in tobacco is responsible for the vast majority of squamous cell carcinoma of the head and neck (SCCHN). Slaughter hypothesized that because of constant carcinogenic pressure, the entire upper aerodigestive tract is at increased risk of developing multiple primary tumors. The original hypothesis was that multiple genetic events occurred throughout the involved mucosa, allowing the development of multiple, molecularly distinct lesions. Recently, however, an alternative hypothesis has been postulated to explain field carcinogenesis. According to it, a single lesion is thought to form multiple upper aerodigestive tract lesions through the process of intraepithelial migration.
SCC arising in nonsmokers
Though SCCHN has been strongly linked to tobacco, a disturbing trend has been observed recently: An increase in incidence among nonsmokers. In the absence of carcinogenic pressure from tobacco, several causative agents have been theorized to play a role in the pathogenesis of these cancers. These include the consumption of alcohol, human papillomavirus (HPV) infection, exposure to secondhand smoke, imbalance of vitamins, immunosuppression, and genetic susceptibility. , Lindel et al.  showed that oral cancers in nonsmokers were more likely to be associated with HPV-positive cancers compared to smokers. Currently, sequences for more than 100 different serotypes of HPV have been identified. They are subdivided on the basis of cutaneous and mucosal site of involvement as high-, intermediate-, and low-risk, depending on their association with malignancy. The transforming potential of high-risk HPVs is largely a result of the function of two viral oncoproteins, namely E6 and E7. ,
| Hallmarks of Oral Cancer|| |
Acquisition of autonomous proliferative signaling
Epidermal growth factor (EGF) axis
The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor that belongs to the HER/erbB family and is overexpressed in up to 90% of SCCHN. A high EGFR gene copy number has been reported in 10-58% of SCCHN. In SCCHN, in contrast to lung cancer, activating EGFR mutations are rare and overexpressions of EGFR and high EGFR gene copy number are also associated with poor prognosis and radioresistance. The EGFR is a relevant target in SCCHN, as cetuximab, an immunoglobulin G1 (IgG1) monoclonal antibody that targets the EGFR, improves overall survival when combined with radiotherapy (RT) or chemotherapy. However, only a minority of patients will benefit from anti-EGFR monoclonal antibodies, and the objective response rate in monotherapy is 6-13%. 
Signal transducers and activators of transcription proteins
The transcription factor signal transducers and activators of transcription 3 (STAT3), which has been detected in many types of cancer, plays an important role in tumor cell survival, proliferation, self-renewal, and invasion.  The activation of STAT3 causes a significant decrease in apoptosis, inhibition of cell cycle progression by activation of caspase 3, and decreased expression of B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-XL), Myeloid cell leukemia 1 (Mcl-1), cyclin D3 (CCND3), and Myc myelocytomatosis oncogene (c-myc). It appears that this downregulation is due to elevated levels of the antiapoptotic protein Bcl-XL. ,, In one of the studies conducted by Tatsuhito Nagumo, it was seen that treatment with JSI-124, which is a specific inhibitor of STAT3, resulted in a decrease of phosphorylated STAT3 and a downregulated expression of survivin, a downstream molecule of the STAT3 signaling cascade. He suggests that the inhibition of STAT3 signaling by JSI-124 might be promising as a molecular therapy strategy against OSCC. 
Nuclear factor-kappa B (NF-kB)
NF-kB may promote tumor progression of SCC through the enhancement of tumor survival and expression of cytokines and other genes. , In this study, 85% of tumors showed increase in the nuclear localization of NF-kB with stronger immunostaining, and was associated with worst prognosis. 
Fibroblast growth factors 
The expression of fibroblast growth factors (FGFs) FGF-1 and FGF-2 is elevated compared with the levels of those in normal mucosa, which was seen by investigators studying cell lines as well as primary tumors of SCC.
Hepatocyte growth factor (HGF) axis 
The HGF receptor has been found to be coded by the c-Met proto-oncogene. Invasion and metastasis of oral cavity cancer cell lines has implicated both HGF and c-Met in recent studies. This increase in invasiveness may be due to HGF's ability to upregulate both matrix metalloproteinase-1 (MMP-1) and MMP-9.  In addition, Dong et al. have shown that a role may be played by HGF in angiogenesis in SCCHN via upregulation of the proangiogenic cytokine interleukin 8 (IL-8) and the vascular endothelial growth factor (VEGF). 
Inhibition of growth inhibitory signals
The TP53 gene that encodes the p53 protein is an important tumor suppressor.  It is estimated that of over 50% of human tumors that harbor mutations in the TP53 gene have dysfunctional p53 signaling. Thus, p53 is also an important candidate target for cancer gene therapy as it participates in all steps of tumor initiation and development by regulating the expression of many downstream genes.  Boyle et al. found that TP53 mutations were there in 19% of premalignant lesions and 43% of malignant lesions. 
INK4 gene family
The INK4 (inhibitors of CDK4) family of genes consists of several proteins - pl5INK4B, pl6INK4A, pl8 INK4C, pl9 INK4D - that appear to act mainly on the G1 phase in the cell cycle. P16 activity was lost in the wide number of primary tumors.  The frequent finding of pl6 gene mutations or the loss of its expression in dysplastic as well as neoplastic oral lesions indicates that this may be an early step in oral carcinogenesis. 
In a study conducted in a Taiwanese population, it was seen that OSCC showed overexpression of cyclin D1 protein, which was significantly associated with lymph node metastasis, and tumor cell differentiation and stage. , Overexpression of cyclin D1 when compared to normal mucosa showed a direct positive correlation with poor prognosis. 
An important role is played by p21 by inhibiting cell apoptosis or resistance to therapy. Patients with a high p21 expression level must be administered intensive combined therapy and provided with follow-ups at an increased frequency to improve overall survival rates. 
Evasion of programmed cell death (apoptosis)
The balance between the proliferation and death of tumor cells depicts the rate of tumor growth. It is known that the Bcl-2 protein is a death antagonist, whereas the Bax, caspase-3, and p53 proteins are death-promoting factors. 
A small amount of telomeric DNA that acts as a protective cap is lost with each replicative cycle. Cell death occurs once enough has been lost. Telomerase activity was found in 100% of cell lines and 90% of invasive cancers but was not detected in any normal tissues in an analysis of 16 SCCHN cell lines and 29 tumor specimens.
Acquisition of a nutrient blood supply (angiogenesis)
The formation of new blood vessels is critical as the tumors grow, invade, and metastasize. Tumors larger than 1 mm 3 may undergo necrosis without adequate vascularization. This process is a multistep process, which appears to be regulated by factors that are both stimulatory and inhibitory. 
Conflicting results have been shown by several studies that looked at microvessel density in relation to the clinical outcome of patients with SCCHN. A correlation between elevated microvessel density, as determined by factor VIII staining, and the development of cervical metastases was shown in one study of 25 patients with stage 2 lesions of the oral cavity.  Another study found that patients who had SCCHN with low microvessel density had a worse prognosis, with a median survival of 10 months, than did patients with increased microvessel density, with a median survival of 69 months. 
Regulators of angiogenesis
A few of these molecules and their purported roles in the angiogenic pathway, with special reference to SCCHN, are discussed below:
Positive regulators of angiogenesis
Various studies have identified that VEGF acts as the most significant predictor of poor prognosis in patients with oral or oropharyngeal carcinoma. 
ii. Platelet-derived endothelial cell growth factor (PD-ECGF)
PD-ECGF was found to be overexpressed in a high percentage of tumor cells, in 58 patients with oral or oropharyngeal cancers. Those patients with lower percentages of tumor cells expressing PD-ECGF had lower rates of relapse and death from their disease than did those with a higher degree of staining. 
Negative regulators of angiogenesis
i. Interferons (IFNs)
Studies of IFNs have shown that the members of this family of cytokines have potent antiangiogenic activity.  Decreased IFN-P expression has been inversely correlated with microvessel density and new blood vessel formation 
ii. Thrombospondins (TSPs)
Two members of the TSP family - TSP-1 and TSP-2 - are also naturally occurring inhibitors of angiogenesis.  Evidence shows that TSP-1 inhibits angiogenesis by inducing endothelial cell apoptosis. 
Tissue invasion and metastasis 
The three steps critical to epithelial tumor cell invasion are the attachment of tumor cells to the basement membrane, proteolysis of the extracellular matrix, and migration of the tumor cell.
Integrins are a family of cell adhesion molecules, and the α6β4 integrin is also known to bind specifically to laminin.  The initial loss of α6β4 is associated with tumor growth in SCC. The expression of α6β4 is frequently enhanced in SCCs and correlates with poor prognosis in patients. 
It plays an important role in maintaining cell-to-cell contacts; increased tumor burden and nodal metastasis seen in the late clinical stage was associated with a significant loss of E-cadherin membranous expression, which was observed in hyperplasia as compared to the normal oral tissues. 
The results from this study indicate that reduced β-catenin protein in OSCC may disrupt stability and integrity of the E-cadherin/catenin complex and disturb cellular adherens junctions. This results in the dissociation of the tumor cells from primary sites, thereby allowing metastases. Invasive growth is the other main characteristic of malignant tumors. Downregulation of β-catenin expression is associated with increased invasiveness. 
Proteolysis and migration
In patients with oral cavity tumors, the expression of this group of enzymes has been correlated with the development of cervical lymph node metastases and lymphatic and vascular invasion. 
Urokinase-type plasminogen activator (uPA)
Patients with uPA receptor (uPAR)-negative tumors had a higher life expectancy than those with uPAR-positive tumors.  The Kaplan-Meier correlation curve showed that there is a statistical correlation that subjects with grade 1 had a shorter overall survival rate, for uPAR-positive patients, while no correlation was found with grades 2 and 3. This may be potentially relevant for the implementation of closer follow-up protocols and/or alternative therapeutic regimens, especially for patients diagnosed with grade 1 tumors. 
Immunohistochemical techniques have shown that patients with oral SCC tumors having high maspin (mammary serine protease inhibitor, a member of the serpin family) expression had lower rates of regional metastases and better overall survival rates, but this indicated that invasive OSCC showed overexpression of SerpinB1 compared to normal oral mucosa. ,
| Conclusion|| |
The past decade has brought about an explosion of information about the pathogenesis of cancer in general and of SCCHN specifically. As more studies correlating clinical outcome with specific molecular aberrations are completed, molecular diagnosis will play an increasingly important role in determining the prognosis and need for specific treatments for patients with SCCHN.
| References|| |
Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol 2009;45:309-16.
Wong DT, Todd R, Tsuji T, Donoff RB. Molecular biology of human oral cancer. Crit Rev Oral Biol Med 1996;7:319-28.
Rasool M, Khan SR, Malik A, Khan KM, Zahid S, Manan A, et al
. Comparative studies of salivary and blood sialic acid, lipid peroxidationand antioxidative status in Oral Squamous Cell Carcinoma (OSCC). Pak J Med Sci 2014;30:466-71.
Singla U, Kulhari S. Genetics - need to evaluate its role in early detection of oral squamous cell carcinoma (OSCC). J Oral Health Comm Dent 2007;1:30-2.
Albertson DG, Collins C, Mccormick F, Gray JW. Chromosome aberrations in solid tumors. Nat Genet 2003;34:369-76.
Jiang Q, Yu YC, Ding XJ, Luo Y, Ruan H. Bioinformatics analysis reveals significant genes and pathways to target for oral squamous cell carcinoma. Asian Pac J Cancer Prev 2014;15:2273-8.
Nowell PC. Mechanisms of tumor progression.Cancer Res 1986;46:2203-7
Myers EN, Suen JY, Myers JN, Hanna EY. Cancer of Head and Neck. 4 th
ed. Chapter: genetics and hallmarks of cancer: Saunders Publication; 1996. p. 7-11.
Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953;6:963-8.
Khode SR, Dwivedi RC, Rhys-Evans P, Kazi R. Exploring the link between human papilloma virus and oral and oropharyngeal cancers. J Can Res Ther 2014;10:492-8.
Castro TB, Galbiatti AL, Raposo LS, Maniglia JV, Pavarino EC, Goloni-Bertollo EM. Head and neck squamous cells carcinoma, DNMT3B gene and folate pathway: A review. Head Neck Oncol 2014;6:17.
Lindel K, Beer KT, Laissue J, Greiner RH, Aebersold DM. Human papillomavirus positive squamous cell carcinoma of the oropharynx: A radiosensitive subgroup of head and neck carcinoma. Cancer 2001;92:805-13.
Zaravinos A. An updated overview of HPV-associated head and neck carcinomas. Oncotarget 2014;5:3956-69.
Machiels JP, Lambrecht M, Hanin FX, Duprez T, Gregoire V, Schmitz S, et al
. Advances in the management of squamous cell carcinoma of the head and neck. F1000Prime Rep 2014;6:44.
Zhao Y, Zhang J, Xia H, Zhang B, Jiang T, Wang J, et al
. Stat3 is involved in the motility, metastasis and prognosis in lingual squamous cell carcinoma. Cell Biochem Funct 2012;30:340-6.
Siavash H, Nikitakis NG, Sauk JJ. Signal transducers and activators of transcription: Insights into the molecular basis of oral cancer. Crit Rev Oral Biol Med 2004;15:298-307.
Mitchell TJ, John S. Signal transducer and activator of transcription (STAT) signalling and T-cell lymphomas. Immunology 2005;114:301-12.
Xiong A, Yang Z, Shen Y, Zhou J, Shen Q. Transcription factor STAT3 as a novel molecular target for cancer prevention. Cancers (Basel) 2014;6:926-57.
Nagumo T, Ito D, Tsukamoto H, Yasudaa A, Shintania S. STAT3 as a target of molecular targeting therapy for oral cancer: Cell-based screening using inhibitor screening kits. Asian Journal of Oral and Maxillofacial Surgery 2011;23:167-71.
Dong G, Chen Z, Kato T, Van Waes C. The host environment promotes the constitutive activation of nuclear factor-kappab and proinflammatory cytokine expression during metastatic tumor progression of murine squamous cell carcinoma. Cancer Res 1999;59:3495-504.
Lee TL, Yang XP, Yan B, Friedman J, Duggal P, Bagain L, et al
. A novel nuclear factor-kappaB gene signature is differentially expressed in head and neck squamous cell carcinomas in association with TP53 status. Clin Cancer Res 2007;13:5680-91.
Zhang PL, Pellitteri PK, Law A, Gilroy PA, Wood GC, Kennedy TL, et al
. Over expression of phosphorylated nuclear factor-kappaB in tonsillar squamous cell carcinoma and high-grade dysplasia is associated with poor prognosis. Mod Pathol 2005;18:924-32.
Haugsten EM, Wiedlocha A, Olsnes S, Wesche J. Roles of fibroblast growth factor receptors in carcinogenesis. Mol Cancer Res 2010;8:1439-52.
Eder JP, Vande Woude GF, Boerner SA, LoRusso PM. Novel therapeutic inhibitors of the c-Met signalling pathway in cancer. Clin Cancer Res 2009;15:2207-14.
Xu Y, Fisher GJ. Role of met axis in head and neck cancer. Cancers (Basel) 2013;5:1601-18.
Dong G, Chen Z, Li ZY, Yeh NT, Bancroft CC, Van Waes C. Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3k signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma. Cancer Res 2001;61:5911-8.
Feng Z, Zhang C, Wu R, Hu W. Tumor suppressor p53 meets micro RNAs. J Mol Cell Biol 2011;3:44-50.
Boyle JO, Hakim J, Koch W, van der Riet P, Hruban RH, Roa RA, et al
. The Incidence of p53 mutations increases with progression of head and neck caancer. Cancer Res 1993;53:4477-80.
Cheng Y. Tumor Suppressor Genes. 1 st
ed. Intech Publisher. p. 344.
Huang SF, Cheng SD, Chuang WY, Chen IH, Liao CT, Wang HM, et al
. Cyclin D1 over expression and poor clinical outcomes in Taiwanese oral cavity squamous cell carcinoma. World J Surg Oncol 2012;10:40.
Khoo ML, Beasley NJ, Ezzat S, Freeman JL, Asa SL. Overexpression of cyclin D1 and underexpression of p27 predict lymph node metastases in papillary thyroid carcinoma. J Clin Endocrinol Metab 2002;87:1814-8.
Swaminathan U, Joshua E, Rao UK, Ranganathan K. Expression of p53 and Cyclin D1 in oral squamous cell carcinoma and normal mucosa: An immunohistochemical study. J Oral Maxillofac Pathol 2012;16:172-7.
Zhang M, Li J, Wang L, Tian Z, Zhang P, Xu Q, et al
. Prognostic significance of p21, p27 and survivin protein expression in patients with oral squamous cell carcinoma. Oncol Lett 2013;6:381-6.
Kurabayashi A, Furihata M, Matsumoto M, Ohtsuki Y, Sasaguri S, Ogoshi S. Expression of Bax and apoptosis-related proteins in human esophageal squamous cell carcinoma including dysplasia. Mod Pathol 2001;14:741-7.
Mehrotra R, Vasstrand EN, Ibrahim SO. Recent advances in understanding carcinogenicity of oral squamous cell carcinoma: From basic molecular biology to latest genomic and proteomic findings. Cancer Genomics & Proteomics 2004;1:283-94.
Rao V, Shenoy A, Karthikeyan B. Role of angiogenetic markers to predict neck node metastasis in head and neck cancers. J Cancer Res Ther 2010;6:142-7.
Shpitzer T, Chaimoff M, Gal R, Stern Y, Feinmesser R, Segal K. Tumor angiogenesis as a prognostic factor in early oral tongue cancer. Arch Otolaryngol Head Neck Surg 1996;122:865-8.
Zätterström UK, Brun E, Willén R, Kjellén E, Wennerberg J. Tumor angiogenesis and prognosis in squamous cell carcinoma of the head and neck. Head Neck 1995;17:312-8.
Walk EL, Weed SA. Recently identified biomarkers that promote lymph node metastasis in head and neck squamous cell carcinoma. Cancers (Basel) 2011;3:747-72.
Tsuzuki H, Sunaga H, Ito T, Narita N, Sugimoto C, Fujieda S. Reliability of platelet-derived endothelial cell growth factor as a prognostic factor for oral and oropharyngeal carcinomas. Arch Otolaryngol Head Neck Surg 2005;131:1071-8.
Indraccolo S. Interferon-alpha as angiogenesis inhibitor: Learning from tumor models. Autoimmunity 2010;43:244-7.
Lee S, Margolin K. Cytokines in cancer immunotherapy. Cancers (Basel) 2011;3:3856-93.
Mirochnik Y, Kwiatek A, Volpert OV. Thrombospondin and apoptosis: Molecular mechanisms and use for design of complementation treatments. Curr Drug Targets 2008;9:851-62.
Nör JE, Mitra RS, Sutorik MM, Mooney DJ, Castle VP, Polverini PJ. Thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway. J Vasc Res 2000;37:209-18.
Danen EH. Integrin signaling as a cancer drug target. ISRN Cell Biol 2013;1-14.
Kaur J, Sawhney M, DattaGupta S, Shukla NK, Srivastava A, Walfish PG, et al
. Clinical significance of altered expression of β-Catenin and E-Cadherin in oral dysplasia and cancer: Potential link with ALCAM expression. PLoS One 2013;8:e67361.
Cai ZG, Shi XJ, Gao Y, Wei MJ, Wang CY, Yu GY. Beta-catenin expression pattern in primary oral squamous cell carcinoma. Chin Med J (Engl) 2008;121:1866-70.
Lindberg P, Larsson A, Nielsen BS. Expression of plasminogen activator inhibitor-1, urokinase receptor and laminin gamma-2 chain is an early coordinated event in incipient oral squamous cell carcinoma. Int J Cancer 2006;118:2948-56.
Bacchiocchi R, Rubini C, Pierpaoli E, Borghetti G, Procacci P, Nocini PF, et al
. Prognostic value analysis of urokinase-type plasminogen activator receptor in oral squamous cell carcinoma: An immunohistochemical study. BMC Cancer 2008;8:220.
Xia W, Lau YK, Hu MC, Li L, Johnston DA, Sheng SJ, et al
. High tumoral maspin expression is associated with improved survival of patients with oral squamous cell carcinoma. Oncogene 2000;19:2398-403.
Tseng MY, Liu SY, Chen HR, Wu YJ, Chiu CC, Chan PT, et al
. Serine protease inhibitor (SERPIN) B1 promotes oral cancer cell motility and is over-expressed in invasive oral squamous cell carcinoma. Oral Oncol 2009;45:771-6.
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