As the most common cancer diagnosed in the oral cavity, tongue squamous cell carcinomas comprise 25%–40% of all oral carcinomas [14
]. The poor prognosis of oral tongue cancer is mainly a consequence of its unusual histological makeup (including a rich lymphatic network and a highly muscularized structure), which makes it poorly equipped to resist invasion and metastasis [15
]. In clinical practice, the most important prognostic factors are tumor size, nodal involvement, and depth of infiltration, although this system cannot reliably predict the clinical outcome or provide useful information concerning the biologic characteristics of the malignancy [5
]. Although some biomarkers correlate with the prognosis of oral tongue cancer, no reliable prognostic biomarkers for oral tongue cancer are available for clinical use. Improving prognostic markers are urgently needed, as survival rates for patients with tumors at the same clinicopathological stage vary considerably.
In the current study, we have demonstrated the clinical significance of GOLPH3 overexpression in cN0 oral tongue cancer for the first time. We also investigated the potential for GOLPH3 expression level to be a clinical prognostic indicator for disease progression and patient survival in cN0 oral tongue cancer. We found that GOLPH3 was highly expressed in cN0 oral tongue cancer cell lines and tissue samples at both the transcriptional and translational levels, and that GOLPH3 protein overexpression correlated with the clinical features of cN0 oral cancer, including clinical stage, T classification, N classification, nodal status, vital status and prognosis. Furthermore, the cumulative 5-year overall and disease-free survival rates of patients with high GOLPH3 expression are lower than those with low or undetectable GOLPH3 expression. Thus, patients with high GOLPH3 expression have a poorer prognosis than those with low or absent GOLPH3 expression, making GOLPH3 a potential independent prognostic factor for cN0 oral tongue cancer.
GOLPH3 was originally identified following proteomic characterization of the Golgi apparatus, and GOLPH3 protein binds to PtdIns(4)P-rich trans-Golgi membranes and MYO18A to provide a tensile force required for efficient tubule and vesicle formation [9
]. GOLPH3 plays an important role in malignant transformation and cell growth by regulating the localization of protein glycosyltransferases to the Golgi [16
]. Recent studies identified a role for GOLPH3 in regulating various biological processes during tumorigenesis and GOLPH3 has been associated with the progression and outcome of many tumor types. An increasing number of studies have found GOLPH3 upregulation in several types of cancers, thus indicating a role for GOLPH3 as a positive regulator of cancer progression.
Furthermore, GOLPH3 overexpression correlates with hyperactivation of mTORC2 and mTORC1 signaling in human cells [12
]. Xenograft experiments revealed that tumor cells overexpressing GOLPH3 have an increased sensitivity to the mTORC1 inhibitor, rapamycin, and GOLPH3-dependent oncogenesis is associated with increased mTOR signaling [13
]. The serine/ threonine protein kinase, mTOR, is a primary regulator of protein synthesis and cell growth that integrates diverse upstream signals including amino acid and energy stress sensing to regulate cell proliferation, growth and survival. The regulation of cell size by mTOR[18
] may be important for cancer development, progression, and metastasis. Cell growth, proliferation, and survival are regulated by a complex network of intracellular and extracellular signal transduction cascades. The growth factor-responsive receptor tyrosine kinase (RTK) phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in governing these processes [15
]. In addition, the serine/threonine kinase AKT functions as a central integrator of RTK–PI3K signaling to modulate downstream effectors, notably the TSC1/2-mTOR complexes. GOLPH3 can enhance downstream growth signaling in response to RTK activation [13
]. We therefore hypothesize that GOLPH3 may affect the development and progression of cN0 oral tongue cancer through the PI3K–AKT–mTOR signaling pathway.
In this study, we investigated GOLPH3 mRNA and protein expression levels in a series of cN0 oral tongue cancer samples. We found that GOLPH3 was highly expressed in cN0 oral tongue cancer cell lines and tissues at both the transcriptional and translational levels, consistent with the hypothesis that GOLPH3 is an oncogene. Elevated levels of GOLPH3 protein positively correlated with several clinicopathologic characteristics of cN0 oral tongue cancer, including pathological stage, T classification, N classification, and nodal status. Moreover, cN0 oral tongue cancer patients with increased GOLPH3 expression had significantly shorter overall and disease-free survival time than patients with lower or no GOLPH3 expression (P
0.010 and P
0.009, respectively). We therefore report that GOLPH3 is a risk factor for cN0 oral tongue cancer, as the upregulation of GOLPH3 in cN0 oral tongue cancer patients indicates a poor prognosis. Thus, the detection of overexpressed GOLPH3 in cN0 oral tongue cancer should identify high-risk tumor phenotypes that require more aggressive primary surgery or adjuvant treatment following surgery. However, while our studies offer some insight into the function of GOLPH3 in tongue squamous cell carcinoma, the underlying mechanism of GOLPH3-mediated oral tongue cancer progression, the role of GOLPH3 in malignant transformation and cell growth and its effects on clinical outcome remain to be defined.
In conclusion, we have demonstrated an important role for GOLPH3 in cN0 tongue carcinogenesis. We suggest that determining GOLPH3 expression levels in cN0 oral tongue cancers may help to identify patients harboring occult micrometastases that require more aggressive treatment and may therefore complement the current TNM classification to enable better risk stratification and election for adjuvant therapy. We further propose that targeting GOLPH3 may be a useful strategy for developing novel therapeutic modalities.