Abstract
BackgroundChronic inflammation is causally linked to the carcinogenesis and progression of most solid tumors. LPTS is a well-identified tumor suppressor by inhibiting telomerase activity and cancer cell growth. However, whether and how LPTS is regulated by inflammation signaling is still incompletely elucidated.MethodsReal-time PCR and western blotting were used to determine the expression of p65 and LPTS. Reporter gene assay, electrophoretic mobility shift assay and chromatin immunoprecipitation were performed to decipher the regulatory mechanism between p65 and LPTS. Cell counting kit-8 assays and xenograt models were used to detect p65-LPTS-regulated cancer cell growth in vitro and in vivo, respectively.ResultsHere we for the first time demonstrated that NF-κB could inhibit LPTS expression in the mRNA and protein levels in multiple cancer cells (e.g. cervical cancer and colon cancer cells). Mechanistically, NF-κB p65 could bind to two consensus response elements locating at −1143/−1136 and −888/−881 in the promoter region of human LPTS gene according to EMSA and ChIP assays. Mutation of those two binding sites rescued p65-suppressed LPTS promoter activity. Functionally, NF-κB regulated LPTS-dependent cell growth of cervical and colon cancers in vitro and in xenograft models. In translation studies, we verified that increased p65 expression was associated with decreased LPTS level in multiple solid cancers.ConclusionsTaken together, we revealed that NF-κB p65 potentiated tumor growth via suppressing a novel target LPTS. Modulation of NF-κB-LPTS axis represented a potential strategy for treatment of those inflammation-associated malignancies.
Highlights
Chronic inflammation is causally linked to the carcinogenesis and progression of most solid tumors
From an open database, we demonstrated that the mRNA level of LPTS was generally decreased in cancer tissues of colon, female reproductive system, kidney, liver, lung, pancreas and stomach, the LPTS expression is increased in breast and prostate cancers (Fig. 1a -b)
To investigate whether inflammatory signaling would regulate LTPS expression, a Human papillomavirus 16 (HPV16)/HPV18-positive cervical carcinoma cell line (CaSki cell) was employed, as Nuclear factor-kappaB (NF-κB) was activated in response to virus infection [35]
Summary
Chronic inflammation is causally linked to the carcinogenesis and progression of most solid tumors. LPTS is a well-identified tumor suppressor by inhibiting telomerase activity and cancer cell growth. Chronic inflammation is causally linked to the carcinogenesis and development of most solid tumors [1,2,3,4,5]. The proinflammatory signal in cancers is characterized by the activated inflammatory pathways (e.g. NF-κB and JNK), elevated inflammatory cytokines (e.g. IL-1β, IL-6 and TNFα) and increased infiltration of immune cells (e.g. macrophages and lymphocytes) [6,7,8]. In response to proinflammatory stimulation, the I-κB kinase is activated to phosphorylate I-κB protein and suppress I-κB-mediated p65 degradation [15]. P65 contains a DNA binding domain and mediates the transcription function of NF-κB in most situations [16]
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