bay-11-7082 and Esophageal-Neoplasms

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent and deadly cancers worldwide, especially in Eastern Asia. It has been indicated that circular RNAs (circRNA) are the key regulators in the development and progression of human cancers. We therefore evaluated the expression and regulation effects of ciRS-7 on the progression of ESCC, which is a recently identified circRNA and acts as a natural competing endogenous RNA. The expression of ciRS-7 was significantly increased in the ESCC tissues and cells as compared with their corresponding controls. In vitro study showed that ciRS-7 can promote the migration and invasion of ESCC cells. Over expression of miR-7, one of well-known targets of ciRS-7, can attenuate ciRS-7 induced invasion of ESCC cells and over expression of matrix metalloproteinase 2 (MMP2). The expression of stem cell marker Kruppel-like factor-4 (KLF-4), which has been reported as the target of miR7, increased significantly in ciRS-7 transfected ESCC cells. Knockdown of KLF-4 also attenuated over expression of ciRS-7 induced cell invasion. In addition, BAY 11-7082, the inhibitor of NF-κB, partially reversed ciRS-7 induced cell invasion. Mechanically studies indicated that ciRS-7 increased the expression of p65 via increasing the phosphorylation of IKK-α. Collectively, our present study revealed that ciRS-7 can trigger the migration and invasion of ESCC cells via miR-7/KLF4 and NF-κB signals. Targeted inhibition of ciRS-7 might be a potential approach for ESCC treatment.

Topics: Cell Line, Tumor; Cell Movement; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagus; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Male; MicroRNAs; Middle Aged; Neoplasm Invasiveness; NF-kappa B; Nitriles; RNA, Circular; RNA, Long Noncoding; Signal Transduction; Sulfones

Esophageal cancer is the eighth most common malignancy, and one of the leading causes of cancer-related deaths worldwide. The overall 5-year survival rate of patients with esophageal cancer remains low at 10% to 40% due to late diagnosis, metastasis, and resistance of the tumor to radiotherapy and chemotherapy. NF-kappaB is involved in the regulation of cell growth, survival, and motility, but little is known about the role of this signaling pathway in the tumorigenesis of human esophageal squamous cell carcinoma (ESCC), the most common form of esophageal cancer. This study aims to explore the functions of NF-kappaB in human ESCC progression and to determine whether targeting the NF-kappaB signaling pathway might be of therapeutic value against ESCC. Our results from human ESCC cell lines and ESCC tissue indicated that NF-kappaB is constitutively active in ESCC. Exposure of ESCC cells to two NF-kappaB inhibitors, Bay11-7082 and sulfasalazine, not only reduced cancer cell proliferation, but also induced apoptosis and enhanced sensitivity to chemotherapeutic drugs, 5-fluorouracil, and cisplatin. In addition, Bay11-7082 and sulfasalazine suppressed the migration and invasive potential of ESCC cells. More importantly, the results from tumor xenograft and experimental metastasis models showed that Bay11-7082 had significant antitumor effects on ESCC xenografts in nude mice by promoting apoptosis, and inhibiting proliferation and angiogenesis, as well as reduced the metastasis of ESCC cells to the lungs without significant toxic effects. In summary, our data suggest that NF-kappaB inhibitors may be potentially useful as therapeutic agents for patients with esophageal cancer.

Topics: Animals; Esophageal Neoplasms; Female; Humans; Immunohistochemistry; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Neovascularization, Pathologic; NF-kappa B; Nitriles; Signal Transduction; Sulfasalazine; Sulfones

Barrett's esophagus, a columnar metaplasia of the lower esophagus epithelium related to gastroesophageal reflux disease, is the strongest known risk factor for the development of esophageal adenocarcinoma (EAC). Understanding the signal transduction events involved in esophageal epithelium carcinogenesis may provide insights into the origins of EAC and may suggest new therapies. To elucidate the molecular pathways of bile acid-induced tumorigenesis, the newly identified inflammation-associated signaling pathway involving I kappaB kinases beta (IKK beta), tuberous sclerosis complex 1 (TSC1), and mammalian target of rapamycin (mTOR) downstream effector S6 kinase (S6K1) was confirmed to be activated in immortalized Barrett's CPC-A and CPC-C cells and esophageal cancer SEG-1 and BE3 cells. Phosphorylation of TSC1 and S6K1 was induced in response to bile acid stimulation. Treatment of these cells with the mTOR inhibitor rapamycin or the IKK beta inhibitor Bay 11-7082 suppressed bile acid-induced cell proliferation and anchorage-independent growth. We next used an orthotopic rat model to evaluate the role of bile acid in the progression of Barrett's esophagus to EAC. Of interest, we found high expression of phosphorylated IKK beta (pIKK beta) and phosphorylated S6K1 (pS6K1) in tumor tissues and the Barrett's epithelium compared with normal epithelium. Furthermore, immunostaining of clinical EAC tissue specimens revealed that pIKK beta expression was strongly correlated with pS6K1 level. Together, these results show that bile acid can deregulate TSC1/mTOR through IKK beta signaling, which may play a critical role in EAC progression. In addition, Bay 11-7082 and rapamycin may potentially be chemopreventive drugs against Barrett's esophagus-associated EAC.

Topics: Adenocarcinoma; Barrett Esophagus; Bile Acids and Salts; Cell Division; Chenodeoxycholic Acid; Esophageal Neoplasms; Gastroesophageal Reflux; Gene Expression Regulation, Neoplastic; Humans; Inflammation; NF-kappa B; Nitriles; Protein Kinases; RNA, Small Interfering; Sirolimus; Sulfones; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins; Ursodeoxycholic Acid