Persistent Krüppel‐like factor 4 expression predicts progression and poor prognosis of head and neck squamous cell carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) is one prevalent human cancer worldwide. No molecular markers are presently used for predicting prognosis in HNSCC. Krü ppel-like factor 4 (KLF4) is a transcription factor with diverse physiological functions, and possesses opposing roles in different human cancers. The expression and roles of KLF4 in HNSCC remain to be elucidated. In this study, immunohistochemical (IHC) analysis of KLF4 in 62 HNSCC was firstly performed. IHC results demonstrated that 42 (67.7%) had decreased KLF4 expression compared with surrounding normal epithelium, while persistent KLF4 expression was demonstrated in 20 (32.3%). The IHC results were further verified by Western blot and real-time PCR analyses to confirm the robustness of staining and interpretation. Interestingly, persistent KLF4 expression independently correlated with a worse disease-specific survival (P = 0.005), especially in patients with advanced disease. In consistent with clinical observation, all five HNSCC cell lines tested revealed a low level of baseline KLF4 expression. Moreover, enforced KLF4 expression in cell line SAS significantly increased in vitro migration ⁄ invasion abilities, multi-drug resistance, and in vivo tumorigenicity. These results clearly illustrate that persistent KLF4 expression predicts poor prognosis and confers aggressiveness in HNSCC. Our data therefore provides valuable information that HNSCC with persistent KLF4 expression might require intensified combination treatment in future practice. (Cancer Sci 2011; 102: 895-902) H ead and neck squamous cell carcinoma (HNSCC) represents the sixth most common malignancy worldwide, and has a profound impact on quality of life.(1) Despite advances in diagnosis and treatment, survival rates of HNSCC have only marginally improved in recent decades.(2) TNM staging system is the current standard for prognostication, which relies heavily on clinical, radiologic and histopathologic parameters. However, substantial heterogeneity is frequently observed in patients of the same risk group. Thus, identifying novel biomarkers will be very useful to improve clinical diagnosis and patient stratification. Krüppel-like factor 4 (KLF4), also known as gut-enriched Krüppel-like factor or epithelial zinc finger, is a zinc finger transcription factor that is physiologically expressed in differentiated epithelium of the gastrointestinal (GI) tract, skin and vascular endothelium.(4,5) KLF4 is primarily regarded as a negative regulator of cell growth, with its ability to regulate the expression of a number of genes involved in cell cycle progression.(6,7) It also plays crucial roles in other physiologic processes, including development, differentiation and tissue homeostasis.(8) Recently, KLF4 has been recognized as one of the genes that can reprogram somatic cells into inducible pluripotent stem cells.(9-11) Overall, these data indicate that the functions of KLF4 are diverse and cell-type specific.Malignant transformation and progression of cancer cells require the accumu...

Expression levels of SOX2, KLF4 and brachyury transcription factors are associated with metastasis and poor prognosis in oral squamous cell carcinoma

“…Furthermore, the association identified between high KLF4 EI and decreased five-year disease-free survival rate in OSCC patients is A B C consistent with the association between increased nuclear expression of KLF4 and poor prognosis in breast cancer and head and neck cancer patients, which has been reported in previous studies (38,39).…”

Expression of Krüppel-like factor 4 in breast cancer tissues and its effects on the proliferation of breast cancer MDA-MB-231 cells

“…KLF4 is expressed at a low level in many types of human malignant tumors accompanied by hypermethylation and loss of heterozygosity (14,15) and has inhibitory effects on gastric (16), colorectal (17), bladder (18) and lung (19) cancer. However, it is highly expressed in ductal carcinoma in situ and in oral squamous cell carcinoma compared with those in normal tissues (20,21). For example, KLF4 overexpression leads to squamous cell carcinoma by inducing hyperplasia and dysplasia (22).…”

Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis

“…Negative regulation of KLF4 by Notch signalling has been observed in intestinal epithelium or colorectal cancer cells 37,38 and these results are in favour of the tumour suppressor role of KLF4 in colorectal cancer cells 39 . In contrast to the tumour suppressor role of KLF4 in colorectal cancer cells/intestinal epithelium and pancreatic cancer [37][38][39][40][41] , other groups have demonstrated the oncogenic role of KLF4 in breast cancer and HNC [42][43][44] . These findings are consistent with our discovery that KLF4 plays an oncogenic role, especially in HNSCC 44 .…”

“…In contrast to the tumour suppressor role of KLF4 in colorectal cancer cells/intestinal epithelium and pancreatic cancer [37][38][39][40][41] , other groups have demonstrated the oncogenic role of KLF4 in breast cancer and HNC [42][43][44] . These findings are consistent with our discovery that KLF4 plays an oncogenic role, especially in HNSCC 44 . In accordance with the general perception, KLF4 should be deemed as a context-specific oncogene or tumour suppressor gene, depending on the tumour cell types.…”