Abstract
BackgroundCLCA2 was reported as a tumor suppressor and disregulated in breast cancer. However, its function in tumor growth and metastasis in NPC has rarely been reported. In this study, we investigated the functional and molecular mechanisms by which CLCA2 influences NPC.MethodsCLCA2 expression in human NPC cell lines and tissues was examined via real-time PCR (RT-PCR), Western blot and IHC. The biological roles of CLCA2 in proliferative, migration and invasion of NPC cell lines was evaluated in 5-8F, S18, S26 and SUNE-1 cells. Cell viability, migration and invasion were assessed in vitro by MTS, colony formation and transwell assay, respectively. CLCA2 in growth and metastasis of NPC were evaluated in vivo through NPC xenograft tumor growth, lung metastatic mice model and popliteal lymph node (LN) metastasis model.ResultsOverexpression of CLCA2 significantly decreased proliferation, migration and invasion of NPC cells. In contrast, knockdown of CLCA2 elicited the opposite effects. CLCA2 overexpression suppressed xenograft tumor growth and lung, popliteal lymph node (LN) metastasis in vivo. CLCA2 inhibited tumor metastasis through suppressing epithelial-Mesenchymal transition (EMT) and in-activating FAK/ERK1/2 signaling pathway in NPC cells. Immunohistochemical staining of 143 NPC samples revealed that CLCA2 expression was an independent, favorable prognostic factor for overall survival and distant metastasis-free survival of patients. In addition, inhibition of FAK and ERK1/2 reversed CLCA2 silencing-induced tumor cell migration. Furthermore, inhibitors against chloride channels suppressed NPC cellular migration which could have been enhanced by the presence of CLCA2.ConclusionCLCA2 suppress NPC proliferation, migration, invasion and epithelial-mesenchymal transition through inhibiting FAK/ERK signaling.
Highlights
CLCA2 was reported as a tumor suppressor and disregulated in breast cancer
Cell lines and culture Four kinds of Nasopharyngeal carcinoma (NPC) cell lines SUNE-1, 5-8F, S26, S18 were cultured in DMEM (Gibco, USA) supplemented with 10% Fetal Bovine Serum (FBS, Gibco) with 100 IU/ ml streptomycin and 100 IU/ml penicillin, all cells were cultured in a humidified atmosphere of 5% CO2 at 37 ° C. (S26 and S18 were isolated from their parental line CNE-2 [19], and 5-8F from its parental line SUNE-1 by limited dilution method [21])
Reduced expression of CLCA2 in primary nasopharyngeal carcinoma correlates with distant metastasis and poor prognosis in NPC patients To evaluate the expression level of CLCA2 in NPC tissue, we performed IHC staining in 143 human NPC samples
Summary
CLCA2 was reported as a tumor suppressor and disregulated in breast cancer. its function in tumor growth and metastasis in NPC has rarely been reported. Despite great improvements in radiotherapy and chemoradiotherapy for NPC [5, 6], the outcome of patients with locoregionally advanced NPC is still unsatisfying [7] This is in part due to the limited efficacy of current therapies against metastasis as well as the emergence of resistance to existing treatments [8, 9]. For these reasons, exploring the molecular mechanisms underlying NPC progression and metastasis to identify new theranostic targets is critical to improving NPC treatment outcomes. Several studies have shown that inhibiting the EMT process can suppress pulmonary metastasis of tumor cell-bearing nude nice [14], indicating the potential clinical value of targeting EMT in cancer treatment
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