title: Activation of interleukin-6/signal transducer and activator of transcription 3 by human papillomavirus early proteins 6 induces fibroblast senescence to promote cervical tumourigenesis through autocrine and paracrine pathways in tumour microenvironment.
abstract: Although it is reported that interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) is activated by human papillomavirus (HPV) infection in cervical cancer cells, little is known about the role of IL-6/STAT3 in tumour microenvironment during development of the disease. In this study, we found that cancer-associated fibroblasts (CAF) but not normal fibroblasts (NF) secrete high level of IL-6 with activated STAT3 and appear senescent at early passages in culture or in cervical cancer tissues infected with high-risk HPV, and that treatment of NF with recombinant IL-6 or CAF conditioned medium (CM) induces activation of STAT3 and cellular senescence. IL-6 and STAT3 are either upregulated or activated in Siha and Hela cells infected with HPV 16 or 18, but not in C33A and ME180 cells without HPV 16 or 18 infection. Overexpression of HPV early proteins 6 (E6) activates STAT3, increases IL-6 expression and tumour burden in C33A and ME180 cells, while silencing of HPV E6 by specific shRNA reduces STAT3 activation, IL-6 expression, and tumour formation in Siha and HeLa cells, so does silencing of STAT3 by specific shRNA in HeLa and C33A/E6 cells. The tumour growth of cervical cancer cells reconstituted with CAF or NF is largely affected by inhibition of fibroblast senescence with STAT3 inhibitor or with IL-6 antibody treatment. Thus, we have uncovered a mechanism that fibroblast senescence promotes cervical cancer development through high-risk HPV E6-activated IL-6/STAT3 signalling in tumour microenvironment.
authors: Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Gynecology and Obstetrics, People's Hospital of Wuxi, Wuxi 214000, China.
authors: Chunxia
authors: C
authors: Ren
authors: Xi
authors: X
authors: Cheng
authors: Bei
authors: B
authors: Lu
authors: Gong
authors: G
authors: Yang
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D052162:Human papillomavirus 16 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D052161:Human papillomavirus 18 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D019899:Paracrine Communication; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology
chemical_list: D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; D015850:Interleukin-6; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: Cervical cancer; Fibroblast senescence; HPV E6; IL-6; STAT3