Expression of Oct3/4 and Nanog in the head and neck squamous carcinoma cells and its clinical implications for delayed neck metastasis in stage I/II oral tongue squamous cell carcinoma

Abstract

BackgroundThe side population (SP) of cancer cells is reportedly enriched with cancer stem cells (CSCs), however, the functional role and clinical relevance of CSC marker molecules upregulated in the SP of head and neck squamous carcinoma (HNSCC) cells are yet to be elucidated. Patients with clinical stage I/II (T1-2N0M0) tongue squamous cell carcinoma (TSCC) typically undergo partial glossectomy; however, development of delayed neck metastasis (DNM) tends to reduce their survival. In the present study, we aimed to determine the CSC markers in the SP of HNSCC cells along with their functions in cellular behaviors, and to clarify the association of these markers with DNM.MethodsFlow cytometry was applied to isolate SP from main population (MP) in HNSCC cells. The expression of the CSC markers was examined by semi-quantitative RT-PCR and immunocytochemistry. In vitro proliferation, migration, and invasion assays were performed to assess cellular behaviors. Clinicopathological factors and immunohistochemical expressions of Oct3/4 and Nanog were evaluated using surgical specimens from 50 patients with stage I/II TSCC.ResultsSPs were isolated in all three cell lines examined. Expression levels of Oct3/4 and Nanog were higher in SP cells than MP cells. Additionally, cell migration and invasion abilities were higher in SP cells than MP cells, whereas there was no difference in proliferation. Univariate analysis showed that expression of Oct3/4 and Nanog, vascular and muscular invasion, and mode of invasion were significantly correlated with DNM. Multivariate logistic regression revealed that Oct3/4 expression (risk ratio = 14.78, p = 0.002) and vascular invasion (risk ratio = 12.93, p = 0.017) were independently predictive of DNM. Regarding the diagnostic performance, Oct3/4 showed the highest accuracy, sensitivity, and NPV of 82.0 %, 61.5 %, and 86.8 %, respectively, while vascular invasion showed the highest specificity and PPV of 94.6 % and 71.4 %, respectively.ConclusionThese results suggest that Oct3/4 and Nanog represent probable CSC markers in HNSCC, which contribute to the development of DNM in part by enhancing cell motility and invasiveness. Moreover, along with vascular invasion, expression of Oct3/4 can be considered a potential predictor for selecting patients at high risk of developing DNM.

Stem cell markers as a resource to predict prognosis of betel quid induced oral squamous cell carcinoma: an immunohistochemical investigation

“…[ [15][16][17][18] Etiological differences may have contributed to this result. In addition, majority of the tumors in the present study sample contained buccal mucosal cancers; while the literature quoted above have focused on tongue cancers.…”

“…In addition, majority of the tumors in the present study sample contained buccal mucosal cancers; while the literature quoted above have focused on tongue cancers. [16,18] Furthermore, Sox-2 expression has been shown to be related to poor survival at sites such as esophagus and bladder as well. [19,20] In addition, problems highlighted below concerning survival data may have also contributed to this result.…”

PTK7 is a molecular marker for metastasis, TNM stage, and prognosis in oral tongue squamous cell carcinoma

“…Nguyen et al reported their experience in providing effective and well-tolerated 0-7-21 palliative radiotherapy to patients with head and neck cancers [20].However,amongstageItonguecarcinomasthereisasubgroupoftumorsthatareprone tolymphnodemetastasisandlocalrecurrence.Ifthis more aggressive tumor behavior could be predicted,patientswhoareatincreasedriskoflymphnode metastasis and recurrence could be subjected to extendedtreatment,whereasthosewithlessaggressive carcinomas could be spared the morbidity associated with such treatment. Many attempts have been madetopredicttheoutcomefortonguecarcinomas throughhistopathologicstudiesandmolecularbiologyanalysis [21,22,23,24].…”

Distinctive properties of metastasis-initiating cells

“…In addition, SOX2 and NANOG have been reported to maintain quiescence programs in DTCs/residual cancer cells and may contribute to metastatic relapse (Sosa et al 2015). Although SOX2, NANOG, OCT4, and KLF4 have been shown to increase metastasis of bladder cancer, breast cancer, lung cancer, and head and neck squamous carcinoma cells (Celia-Terrassa et al 2012;Vaira et al 2013;Lu et al 2014;Habu et al 2015), none of these factors has been specifically studied during metastasis initiation. Based on current knowledge, it is tempting to speculate that these factors may also facilitate metastatic initiation by promoting cell plasticity, adaptability, survival, and self-renewal as they do in primary tumors.…”