Abstract
BackgroundThe functions of the protein expressed in the nucleus and cytoplasm were different or opposite. The previous study found that oncogene Klf4 played a role of tumor suppressor in the nasopharyngeal cytoplasm. Cetuximab targeted epidermal growth factor receptor (EGFR) for the treatment of nasopharyngeal carcinoma.MethodsA cohort of 231 cases of advanced nasopharyngeal carcinoma (7th AJCC III–IVa) samples was assessed by immunohistochemistry (IHC), of which, 63 cases were treated with basic treatment without cetuximab, the basic treatment include chemotherapy and radiotherapy, the regent of the chemotherapy include cisplatin and fluorouracil and 168 cases were treated with cetuximab in addition to the basic treatment. The expression of the KLF4 protein was detected in nucleus and cytoplasm, c-Met protein and nuclear EGFR protein (nEGFR) by IHC, and H-Ras and PI3K mutations by an arms-PCR method in vivo. KLF4 was found to specifically express in the cytoplasm by deleting the NES, while H-Ras and PI3K genes were mutated in the nasopharyngeal carcinoma 5–8F and HONE1cell line. The cetuximab resistance in differentially mutated 5–8F and HONE1 cells was analyzed.ResultsThe expression of Klf4 in the nucleus was associated with prognosis in 168 patients with cetuximab-treated nasopharyngeal carcinoma, which was found by retrospective analysis. The KLF4 expression in the nucleus was not significantly correlated with the prognosis in 63 nasopharyngeal carcinoma patients treated with basic treatment (P = 0.261). The expression of Klf4 in the nucleus was correlated with mutations of H-Ras and PI3K in 168 cases of nasopharyngeal carcinoma with cetuximab treatment. In vitro experiments showed that Klf4 was specifically expressed in the nucleus of 5–8F and HONE1 cells as assessed by deleting nuclear export signal, which led to cetuximab resistance. H-Ras and PI3K mutations in 5–8F and HONE1 cells also led to the expression of Klf4 in the nucleus and resistance to cetuximab. In HONE1 cells, Klf4 was specifically localized in the cytoplasm by deleting the NES, and the H-Ras and PI3K mutations did not result in an increased expression of Klf4 in the nucleus and cetuximab resistance.ConclusionThe prognosis of nasopharyngeal carcinoma was not significantly improved by cetuximab treatment when the Klf4 was highly expressed in the nucleus of nasopharyngeal carcinoma tissues. The expression of Klf4 in the nucleus can be used as a biomarker for predicting the effects of cetuximab treatment in nasopharyngeal carcinoma, which might be attributed to the H-RAS and PI3K mutations, leading to cetuximab resistance.
Highlights
The functions of the protein expressed in the nucleus and cytoplasm were different or opposite
Expression of KLF4 in the nucleus induced a poor prognosis in patients treated with cetuximab Tumor specimen from 168 NPC patients consisting of 94 males and 74 female were included in this study
Patients with basic treatment only showed a high expression of the KLF4 protein in the cytoplasm with a better prognosis than that of the low expression (Fig. 1B-a, P = 0.026), correspondingly, 23 cases showed a high expression of KLF4 in the nucleus but without a significant correlation with prognosis (Fig. 1B-a, P = 0.261)
Summary
The functions of the protein expressed in the nucleus and cytoplasm were different or opposite. Cetuximab targeted epidermal growth factor receptor (EGFR) for the treatment of nasopharyngeal carcinoma. Cetuximab is the only molecular targeted drug approved for the head and neck cancer treatment in clinical practice. It is a human–mouse chimeric antibody that blocks the binding of EGFR [1]. The use of cetuximab to block EGFR has inhibitory effects in most of the nasopharyngeal carcinomas. A large proportion of head and neck tumors are resistant to cetuximab. A large number of molecular markers associated with cetuximab resistance were identified with respect to the nuclear expression of EGFR, H-Ras mutation, PI3K mutation, and c-Met protein overexpression [3,4,5]
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