Prognostic role of Oct4, CD44 and c-Myc in radio–chemo-resistant oral cancer patients and their tumourigenic potential in immunodeficient mice
- First Online:
- 297 Downloads
In the present study, we have investigated the prognostic value of known stem cell-associated molecules such as Oct4, CD44 and c-Myc in patients with oral SCC who had received post-surgery radio- and/or chemotherapy.
Materials and methods
Immunohistochemistry was performed to analyse the expression of Oct4, CD44 and c-Myc in 87 tumour tissues, and the expression profile obtained was correlated with clinicopathological parameters of the patients with oral cancer. Tumourigenic potential of these molecules was also evaluated by in vivo studies.
Our results showed significant correlation of Oct4 (OS, p = 0.003; DFS, p = 0.001) and c-Myc (OS, p = 0.01; DFS, p = 0.03) with overall survival and disease-free survival independently. Furthermore, all the three markers in combinations of two markers each, i.e. Oct4 + CD44 (OS, p = 0.003; DFS, p = 0.001), Oct4 + c-Myc (OS, p = 0.0001; DFS, p = 0.0001), CD44 + c-Myc (OS, p = 0.008; DFS, p = 0.02) and in combinations of three markers each, i.e. Oct4 + CD44 + c-Myc (OS, p = 0.0001; DFS, p = 0.0001) also significantly correlated with overall survival and disease-free survival. Univariate and multivariate analyses further established the independent prognostic value of Oct4. Oct4-, CD44- and c-Myc-enriched populations independently induced sarcomatoid carcinomas whereas primary keratinocytes developed poorly differentiated carcinomas in immunodeficient mice.
Oct4 and c-Myc independently as well as in combination with CD44 might be useful for the prediction of local recurrence and poor survival of patients with oral cancer which is the novel finding of this study.
Oct4, c-Myc and CD44 can be used to predict local recurrence and the outcome of treatment in oral cancer patients. In addition, these molecules may find use as molecular targets for effective therapy.
KeywordsOral cancer Recurrence Cancer stem cells Oct4 CD44 Prognosis
- 4.Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A 104(3):973–978. doi:10.1073/pnas.0610117104 PubMedPubMedCentralCrossRefGoogle Scholar
- 5.Pries R, Witrkopf N, Trenkle T, Nitsch SM, Wollenberg B (2008) Potential stem cell marker CD44 is constitutively expressed in permanent cell lines of head and neck cancer. In Vivo (Athens, Greece) 22(1):89–92Google Scholar
- 6.Huang CF, Xu XR, Wu TF, Sun ZJ, Zhang WF (2014) Correlation of ALDH1, CD44, OCT4 and SOX2 in tongue squamous cell carcinoma and their association with disease progression and prognosis. J Oral Pathol Med Off Publ Int Ass Oral Pathol Am Acad Oral Pathol 43(7):492–498. doi:10.1111/jop.12159 Google Scholar
- 10.Chiou SH, Yu CC, Huang CY, Lin SC, Liu CJ, Tsai TH, Chou SH, Chien CS, Ku HH, Lo JF (2008) Positive correlations of Oct-4 and Nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clin Cancer Res Off J Am Assoc Cancer Res 14(13):4085–4095. doi:10.1158/1078-0432.ccr-07-4404 CrossRefGoogle Scholar
- 17.Ue T, Yokozaki H, Kagai K, Higashikawa K, Yasui W, Sugiyama M, Tahara E, Ishikawa T (1998) Reduced expression of the CD44 variant exons in oral squamous cell carcinoma and its relationship to metastasis. J Oral Pathol Med Off Publ Int Ass Oral Pathol Am Acad Oral Pathol 27(5):197–201Google Scholar
- 20.Oliveira DT, Sherriff M, Odell EW (1998) Expression of CD44 variant exons by primary and metastatic oral squamous carcinomas. J Oral Pathol Med Off Publ Int Ass Oral Pathol Am Acad Oral Pathol 27(7):303–307Google Scholar
- 30.Klinakis A, Szabolcs M, Politi K, Kiaris H, Artavanis-Tsakonas S, Efstratiadis A (2006) Myc is a Notch1 transcriptional target and a requisite for Notch1-induced mammary tumorigenesis in mice. Proc Natl Acad Sci U S A 103(24):9262–9267. doi:10.1073/pnas.0603371103 PubMedPubMedCentralCrossRefGoogle Scholar
- 34.Segura S, Rozas-Munoz E, Toll A, Martin-Ezquerra G, Masferrer E, Espinet B, Rodriguez M, Baro T, Barranco C, Pujol RM (2013) Evaluation of MYC status in oral lichen planus in patients with progression to oral squamous cell carcinoma. Br J Dermatol 169(1):106–114. doi:10.1111/bjd.12303 PubMedCrossRefGoogle Scholar
- 39.Sawant SS, Vaidya M, Chaukar DA, Alam H, Dmello C, Gangadaran P, Kannan S, Kane S, Dange PP, Dey N, Ranganathan K, D’Cruz AK (2014) Clinical significance of aberrant vimentin expression in oral premalignant lesions and carcinomas. Oral Dis 20(5):453–465. doi:10.1111/odi.12151 PubMedCrossRefGoogle Scholar
- 40.Chinn SB, Darr OA, Peters RD, Prince ME (2012) The role of head and neck squamous cell carcinoma cancer stem cells in tumorigenesis, metastasis, and treatment failure. Front Endocrinol 3. doi:10.3389/fendo.2012.00090
- 41.Kosunen A, Pirinen R, Ropponen K, Pukkila M, Kellokoski J, Virtaniemi J, Sironen R, Juhola M, Kumpulainen E, Johansson R, Nuutinen J, Kosma VM (2007) CD44 expression and its relationship with MMP-9, clinicopathological factors and survival in oral squamous cell carcinoma. Oral Oncol 43(1):51–59. doi:10.1016/j.oraloncology.2006.01.003 PubMedCrossRefGoogle Scholar