Weiqiang Huang1, Longshan Zhang1, Mi Yang1, Xixi Wu1, Xiaoqing Wang1, Wenqi Huang2, Lu Yuan2, Hua Pan1, Yin Wang1, Zici Wang3, Yuting Wu2, Jihong Huang2, Huazhen Liang4, Shaoqun Li5, Liwei Liao1, Laiyu Liu6, Jian Guan7. 1. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. 2. Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. 3. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China. 4. Department of Oncology, Maoming People's Hospital, Maoming, Guangdong, China. 5. Department of Radiation Oncology, Guangdong 999 Brain Hospital, Guangzhou, Guangdong, China. 6. Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. liuly5461@163.com. 7. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. guanjian5461@163.com.
Abstract
BACKGROUND: Irradiation has emerged as a valid tool for nasopharyngeal carcinoma (NPC) in situ treatment; however, NPC derived from tissues treated with irradiation is a main cause cancer-related death. The purpose of this study is to uncover the underlying mechanism regarding tumor growth after irradiation and provided potential therapeutic strategy. METHODS: Fibroblasts were extracted from fresh NPC tissue and normal nasopharyngeal mucosa. Immunohistochemistry was conducted to measure the expression of α-SMA and FAP. Cytokines were detected by protein array chip and identified by real-time PCR. CCK-8 assay was used to detect cell proliferation. Radiation-resistant (IRR) 5-8F cell line was established and colony assay was performed to evaluate tumor cell growth after irradiation. Signaling pathways were acquired via gene set enrichment analysis (GSEA). Comet assay and γ-H2AX foci assay were used to measure DNA damage level. Protein expression was detected by western blot assay. In vivo experiment was performed subcutaneously. RESULTS: We found that radiation-resistant NPC tissues were constantly infiltrated with a greater number of cancer-associated fibroblasts (CAFs) compared to radiosensitive NPC tissues. Further research revealed that CAFs induced the formation of radioresistance and promoted NPC cell survival following irradiation via the IL-8/NF-κB pathway to reduce irradiation-induced DNA damage. Treatment with Tranilast, a CAF inhibitor, restricted the survival of CAF-induced NPC cells and attenuated the of radioresistance properties. CONCLUSIONS: Together, these data demonstrate that CAFs can promote the survival of irradiated NPC cells via the NF-κB pathway and induce radioresistance that can be interrupted by Tranilast, suggesting the potential value of Tranilast in sensitizing NPC cells to irradiation.
BACKGROUND: Irradiation has emerged as a valid tool for nasopharyngeal carcinoma (NPC) in situ treatment; however, NPC derived from tissues treated with irradiation is a main cause cancer-related death. The purpose of this study is to uncover the underlying mechanism regarding tumor growth after irradiation and provided potential therapeutic strategy. METHODS: Fibroblasts were extracted from fresh NPC tissue and normal nasopharyngeal mucosa. Immunohistochemistry was conducted to measure the expression of α-SMA and FAP. Cytokines were detected by protein array chip and identified by real-time PCR. CCK-8 assay was used to detect cell proliferation. Radiation-resistant (IRR) 5-8F cell line was established and colony assay was performed to evaluate tumor cell growth after irradiation. Signaling pathways were acquired via gene set enrichment analysis (GSEA). Comet assay and γ-H2AX foci assay were used to measure DNA damage level. Protein expression was detected by western blot assay. In vivo experiment was performed subcutaneously. RESULTS: We found that radiation-resistant NPC tissues were constantly infiltrated with a greater number of cancer-associated fibroblasts (CAFs) compared to radiosensitive NPC tissues. Further research revealed that CAFs induced the formation of radioresistance and promoted NPC cell survival following irradiation via the IL-8/NF-κB pathway to reduce irradiation-induced DNA damage. Treatment with Tranilast, a CAF inhibitor, restricted the survival of CAF-induced NPC cells and attenuated the of radioresistance properties. CONCLUSIONS: Together, these data demonstrate that CAFs can promote the survival of irradiated NPC cells via the NF-κB pathway and induce radioresistance that can be interrupted by Tranilast, suggesting the potential value of Tranilast in sensitizing NPC cells to irradiation.
Authors: Dhruv Kumar; Jacob New; Vikalp Vishwakarma; Radhika Joshi; Jonathan Enders; Fangchen Lin; Sumana Dasari; Wade R Gutierrez; George Leef; Sivapriya Ponnurangam; Hemantkumar Chavan; Lydia Ganaden; Mackenzie M Thornton; Hongying Dai; Ossama Tawfik; Jeffrey Straub; Yelizaveta Shnayder; Kiran Kakarala; Terance Ted Tsue; Douglas A Girod; Bennett Van Houten; Shrikant Anant; Partha Krishnamurthy; Sufi Mary Thomas Journal: Cancer Res Date: 2018-05-16 Impact factor: 12.701
Authors: Sarah Elizabeth Wheeler; Huifang Shi; Fangchen Lin; Sumana Dasari; Joseph Bednash; Stephen Thorne; Simon Watkins; Radhika Joshi; Sufi Mary Thomas Journal: Head Neck Date: 2013-06-01 Impact factor: 3.147