Exposure to TNF-α combined with TGF-β induces carcinogenesis in vitro via NF-κB/Twist axis

Persistent human papilloma virus (HPV) infection induces chronic inflammation resulting in human cervical cancer. However, the mechanisms underlying carcinogenesis via chronic inflammation remain largely unclear. We investigated the role of pro-inflammatory factors in epithelial-mesenchymal transition (EMT) and cancer stem cell-like (CSCL) characteristics of HeLa cells exposed to TNF-alpha with or without TGF-beta. We then determined the role of NF-kappa beta/Twist signal axis in the pathogenesis of cervical cancer. We found that HeLa cells exposed to TNF-a following chronic treatment with TGF-beta exhibited EMT, self-renewal and high mobility. Knockdown of NF-kappa Bp65 inhibited NF-kappa B and Twistl expression, and EMT and CSCL properties of HeLa cells following co-treatment with TNF-alpha and TGF-beta. Conversely, overexpression of NF-kappa Bp65 potentiated the above effects. However, knockdown or overexpression of Twistl had no effect on NF-kappa Bp65 expression, but inhibited or promoted EMT and CSCL features. Notably, overexpression of Twistl rescued NF-kappa Bp65 knockdown. Our results demonstrate the role of NF-kappa B/Twist signaling axis in which HeLa cells treated with TNF-alpha following chronic exposure to TGF-beta induce EMT and CSCL properties. The NF-kappa B/Twist signal axis may represent an effective therapeutic target in cervical cancer.