IKK beta 促進 mTOR 訊息活化以增進肝癌和食道腺癌細胞增生和血管新生因子表現

Abstract

Accumulated evidence suggests that inflammation is associated with human tumors, but the underlying mechanism of tumorigenesis is not yet fully understood. TNFα is considered one of the most important factors involved in inflammation-mediated tumorigenesis, and the transcription factor NF-κB, a downstream signaling transducer of TNFα, has been implicated in oncogenesis by promoting expression of genes related to cell proliferation and survival. Activation of the inhibitor of nuclear factor κB (IκB) kinase (IKK) by TNFα phosphorylates IκBs and promotes degradation of IκBs, resulting in nuclear translocation of NF-κB and induction of NF-κB downstream genes. Tuberous sclerosis complex 1 (TSC1), a well-known tumor suppressor involved in the development of tuberous sclerosis, negatively regulates the mammalian target of rapamycin (mTOR) pathway by inhibiting Ras homolog enriched in brain (RHEB). Deregulation of the TSC/mTOR signaling pathway has been implicated in the development of cancer and the activation of ribosomal protein S6 kinase (S6K1) by mTOR was found to lead to increased cell proliferation and angiogenesis. Our study deals with two important inflammatory associated cancers development. Firstly, bile acid reflux could induce the esophagus inflammation and esophageal adenocarcinoma development. Our study found that the bile acid deregulated the TSC1/mTOR pathway through IKKβ signaling. We found that treatment of Barrett’s esophagus cells and esophageal adenocarcinoma cells with the IKKβ inhibitor Bay 11-7082 or the mTOR inhibitor rapamycin inhibited cell proliferation and in vitro transformation measured by the anchorage-independent growth assay. We next evaluated normal esophageal epithelium, Barrett’s esophagus lesions and tumor samples from patients with Barrett’s esophagus-associated esophageal adenocarcinoma and found a concomitant sustained expression of both, pIKKβ and pS6K1, in Barrett’s esophagus high-grade dysplasia and in esophageal adenocarcinoma. Our results indicate that bile acid may activate the mTOR pathway via IKKβ signaling, leading to Barrett’s esophagus and esophageal adenocarcinoma. Secondly, hepatitis B infection is highly associated with hepatoma development. However the truth oncogenic mechanism is still under study. We investigated whether HBx can modulate IKKβ to inactivate TSC1’s inhibition on mTOR so that it contributes to HCC development. We found that HBx modulated IKKβ/TSC1/mTOR signaling and up-regulated cell proliferation and VEGF production in hepatoma cells. Furthermore, we investigated the status of IKKβ/TSC1/mTOR signaling in specimens from HBV-associated human hepatomas, and analyzed the relationship between the status of IKK/TSC1/mTOR signaling and the prognosis of HCC patients. We conclude that IKKβ activates mTOR signaling through TSC1 suppression to contribute to one crucial mechanism underlying HBx-dependent pathogenesis of HCC. In conclusion, we demonstrate that activation of the IKKβ/mTOR pathway occurs concomitantly with increased cell proliferation and angiogenesis, which may associate with the progression of the hepatoma and esophageal adenocarcinoma. Blocking IKKβ or mTOR signaling with Bay 11-7082 or rapamycin, respectively, inhibits the cancer cell growth and VEGF-A production, suggesting that inhibitors of IKKβ or mTOR signaling may be useful as new therapeutics for the treatment of HBV-associated hepatoma and Barrett’s esophagus- associated esophageal adenocarcinoma.