Nm23‐H1 expression of metastatic tumors in the lymph nodes is a prognostic indicator of oral squamous cell carcinoma

Abstract

We recently reported that low Nm23-H1 expression of primary oral squamous cell carcinoma (OSCC) was correlated with the occurrence of lymphatic metastasis. However, little is known about whether Nm23-H1 level of metastatic tumors in the cervical lymph nodes is reduced in comparison with primary oral cancers and its significance for patients' prognosis. By immunohistochemistry, we analyzed the Nm23-H1 expression in 52 pairs of OSCC specimens from primary oral cancers and their metastatic lymph nodes. Western blot analysis further confirmed the immunohistochemical interpretation. To verify the effects of Nm23-H1 on cell migration and invasion, we established several stable clones derived from a human OSCC cell line (SAS) by knockdown and overexpression. Wound-healing closure, transwell migration and invasion assays were performed to determine cell motility, migratory and invasive activities. Western blot analysis was carried out to evaluate cyclin A expression of OSCC cells with the altered Nm23-H1 levels following knockdown and overexpression. By immunohistochemistry, Nm23-H1 expression of metastatic lymph nodes was significantly lower than that of their primary oral cancers, supporting a role of Nm23-H1 in metastasis suppression. Negative Nm23-H1 interpretation of OSCC specimens, in either primary oral cancers or metastatic lymph nodes, indicated a poor survival outcome of patients. On the basis of in vitro studies of Nm23-H1 knockdown and overexpression, we demonstrated an inverse correlation between Nm23-H1 expression and the invasiveness of OSCC cells. Moreover, we observed the concomitant reduction in Nm23-H1 and cyclin A levels of metastatic tumors in both results of in vitro OSCC cells and ex vivo tumor specimens. ' 2007 Wiley-Liss, Inc.Key words: oral squamous cell carcinoma (OSCC); Nm23-H1; metastasis; cyclin A Oral squamous cell carcinoma (OSCC) is the most common malignant tumor of oral cavity and its incidence ranges from less than 0.1% to over 40% in the world.1,2 In Taiwan, oral cancer has been the fourth or fifth leading cause of cancer death in the males and the seventh in the whole population since 1991. 3Despite of multi-therapeutic modalities, the overall survival of OSCC patients has not improved in the recent 2 decades. 4 One major cause of treatment failure is early metastases of OSCCs. Previous studies reported that more than half of the patients with resectable OSCCs had lymphatic spreading at diagnosis. 5,6 It is clinically relevant to assess whether a patient has or will develop lymphatic metastasis of OSCC. Moreover, there is evidence that a basic mechanism underlies the differential outcomes between patients of a small oral tumor with abundant metastases presenting poorer prognosis and those of a large primary lesion without lymphatic dissemination obtaining better survival. Biomarkers suggestive of the discriminating pathways for predicting disease progression would be imperative to commence optimal treatments and improve therapeutic outcomes.The nm23 was originally identified by diff...

NME1 (NME/NM23 nucleoside diphosphate kinase 1)

“…Remarkably, enforced NME1 expression induced by transfection in epithelial cancer derived cell lines and melanoma reverses their motility and invasive potential. This was observed with cell lines derived from melanoma (Leone et al, 1991) and from breast (Leone et al, 1993a), colon (Suzuki et al, 2004), lung (Nie et al, 2008), liver (She et al, 2010), ovarian (Li et al, 2006), prostate (Andolfo et al, 2011) and oral (Wang YF et al, 2008) carcinomas. In other types of cancers such as neuroblastoma (Leone et al, 1993b;Garcia et al, 2012), hematopoietic malignancies (Yokoyama et al, 1998) and osteosarcoma (Liao et al, 2000), a high tumoral expression was noted which was most often correlated with poor clinical outcome.…”

“…McDonald et al (1996) have shown that a high NME1 expression in the primary tumor predicts a favorable outcome although the reverse was found by another study (Pavelic et al, 2000). Wang YF et al (2008) have observed a low NME1 level in lymph node metastases of patient with oral squamous cell carcinoma and that induced NME1 overexpression in these cancer derived cell lines decreased their invasive potential. In osteosarcoma, a positive immunoreactivity was detected in tumoral cells (Oda et al, 1995;Liao et al, 2000), but no correlation (Liao et al, 2000;Ozger et al, 2009) or a positive correlation (Oda et al, 2000) between NME1 expression and metastatic spread was observed.…”

“…For head and neck squamous cell carcinoma, several studies pointed to the absence of prognostic interest for NME1 (Takes et al, 2001;Tsuzuki et al, 2005;Sheikh et al, 2006;Mhawech-Fauceglia et al, 2007). However, some authors reported a lower NME1 level in lymph nodes as compared to the primary tumor (Takes et al, 2001;Wang YF et al, 2008) or an inverse correlation with lymph node invasion but not associated with better survival (Song et al, 2000). McDonald et al (1996) have shown that a high NME1 expression in the primary tumor predicts a favorable outcome although the reverse was found by another study (Pavelic et al, 2000).…”

High CD10 expression in lymph node metastases from surgically treated prostate cancer independently predicts early death

“…The prognostic potential of biomarker expression in the different tumor components of lymph node positive cancer has been compared in only few tumors [19][20][21] including prostate cancers [22][23][24][25]. In case of successful survival stratification, the metastasizing tumor component but not the primary tumor [19,20,22] or both tumor components [21,23,25] may harbor the prognostic information.…”

Tetraspanin gene expression levels as potential biomarkers for malignancy of gingival squamous cell carcinoma

“…Candidates for biomarkers of head and neck cancers including oral SCC (OSCC) were found in some studies; however, they have not been of practical use. 4,5 Although diagnostic imaging, status of lymph node metastasis and histology still will be clinically essential criteria, they are not able to provide sufficient information to realize the individualized treatment of OSCC in the future. A precise malignancy diagnosis of OSCC, such as prediction of potential metastasis or accurate assessment of treatment sensitivity at the early stage prior to revealing the existence of metastatic focus, enables us to set proper ranges of resection and to plan surgical methods.…”