PMID- 33646559 OWN - NLM STAT- MEDLINE DCOM- 20211213 LR - 20211214 IS - 2211-3436 (Electronic) IS - 2211-3428 (Linking) VI - 44 IP - 3 DP - 2021 Jun TI - COX2 confers bone marrow stromal cells to promoting TNFalpha/TNFR1beta-mediated myeloma cell growth and adhesion. PG - 643-659 LID - 10.1007/s13402-021-00590-4 [doi] AB - PURPOSE: Bone marrow stromal cells (BMSCs) have been implicated in multiple myeloma (MM) progression. However, the underlying mechanisms remain largely elusive. Therefore, we aimed to explore key factors in BMSCs that contribute to MM development. METHODS: RNA-sequencing was used to perform gene expression profiling in BMSCs. Enzyme-linked immunosorbent assays (ELISAs) were performed to determine the concentrations of PGE2 and TNFalpha in sera and conditioned media (CM). Western blotting, qRT-PCR and IHC were used to examine the expression of cyclooxygenase 2 (COX2) in BMSCs and to analyze the regulation of TNFalpha by COX2. Cell growth and adhesion assays were employed to explore the function of COX2 in vitro. A 5T33MMvt-KaLwRij mouse model was used to study the effects of COX2 inhibition in vivo. RESULTS: COX2 was found to be upregulated in MM patient-derived BMSCs and to play a critical role in BMSC-induced MM cell proliferation and adhesion. Administration of PGE2 to CM derived from BMSCs promoted MM cell proliferation and adhesion. Conversely, inhibition of COX2 in BMSCs greatly compromised BMSC-induced MM cell proliferation and adhesion. PCR array-based analysis of inflammatory cytokines indicated that COX2 upregulates the expression of TNFalpha. Subsequent rescue assays showed that an anti-TNFalpha monoclonal antibody could antagonize COX2-mediated MM cell proliferation and adhesion. Administration of NS398, a specific COX2 inhibitor, inhibited in vivo tumor growth and improved the survival of 5TMM mice. CONCLUSIONS: Our results indicate that COX2 contributes to BMSC-induced MM proliferation and adhesion by increasing the secretion of PGE2 and TNFalpha. Targeting COX2 in BMSCs may serve as a potential therapeutic approach of treating MM. FAU - Kuang, Chunmei AU - Kuang C AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital; Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410078, China. FAU - Zhu, Yinghong AU - Zhu Y AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital; Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410078, China. FAU - Guan, Yongjun AU - Guan Y AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital; Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410078, China. FAU - Xia, Jiliang AU - Xia J AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital; Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410078, China. FAU - Ouyang, Jian AU - Ouyang J AD - Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai, 201203, China. FAU - Liu, Guizhu AU - Liu G AD - Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Chinese Academy of Sciences, Shanghai, 200030, China. FAU - Hao, Mu AU - Hao M AD - State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300020, China. FAU - Liu, Jiabin AU - Liu J AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital; Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410078, China. FAU - Guo, Jiaojiao AU - Guo J AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital; Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410078, China. FAU - Zhang, Wenxia AU - Zhang W AD - State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300020, China. FAU - Feng, Xiangling AU - Feng X AD - Xiang Ya School of Public Health, Central South University, Changsha, 410078, China. FAU - Li, Xin AU - Li X AD - Department of hematology, Third Xiangya Hospital, Central South University, Changsha, 410013, China. FAU - Zhang, Jingyu AU - Zhang J AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital; Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410078, China. FAU - Wu, Xuan AU - Wu X AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital; Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410078, China. FAU - Xu, Hang AU - Xu H AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital; Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410078, China. FAU - Li, Guancheng AU - Li G AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital; Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410078, China. FAU - Xie, Lu AU - Xie L AD - Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai, 201203, China. FAU - Fan, Songqing AU - Fan S AD - Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. FAU - Qiu, Lugui AU - Qiu L AD - State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300020, China. FAU - Zhou, Wen AU - Zhou W AUID- ORCID: 0000-0003-4085-7714 AD - The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Department of Hematology, Xiangya Hospital; Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, 410078, China. wenzhou@csu.edu.cn. LA - eng GR - 2018 YFAO107800/Ministry of Science and Technology of China/ GR - 81974010/National Natural Science Foundation of China/ GR - 81800209/National Natural Science Foundation of China/ GR - 81630007/National Natural Science Foundation of China/ GR - 2020WK2006/The Key Technology Research and Development program of the Ministry of Science and Technology of Hunan Province, China/ GR - ZLXD2017004/Fundamental Research Strategic Priority Research Program of Central South University/ GR - ZK16-04/SKLEH-Pilot Research Grant/ GR - 2018zzts235/Fundamental Research Funds for Graduate of Central South University/ GR - 2018zzts079/Fundamental Research Funds for Graduate of Central South University/ GR - 2019zzts087/Fundamental Research Funds for Graduate of Central South University/ PT - Journal Article DEP - 20210301 PL - Netherlands TA - Cell Oncol (Dordr) JT - Cellular oncology (Dordrecht) JID - 101552938 RN - 0 (Receptors, Tumor Necrosis Factor, Type I) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 1.14.99.1 (Cyclooxygenase 2) SB - IM MH - Animals MH - Cell Adhesion/physiology MH - Cell Proliferation/physiology MH - Cyclooxygenase 2/*metabolism MH - Humans MH - Mesenchymal Stem Cells/*metabolism MH - Mice MH - Multiple Myeloma/*pathology MH - Receptors, Tumor Necrosis Factor, Type I/*metabolism MH - Tumor Cells, Cultured MH - Tumor Necrosis Factor-alpha/*metabolism OTO - NOTNLM OT - BMSCs OT - Cyclooxygenase-2 OT - Multiple myeloma OT - TNFalpha EDAT- 2021/03/02 06:00 MHDA- 2021/12/15 06:00 CRDT- 2021/03/01 12:16 PHST- 2021/01/19 00:00 [accepted] PHST- 2021/03/02 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2021/03/01 12:16 [entrez] AID - 10.1007/s13402-021-00590-4 [pii] AID - 10.1007/s13402-021-00590-4 [doi] PST - ppublish SO - Cell Oncol (Dordr). 2021 Jun;44(3):643-659. doi: 10.1007/s13402-021-00590-4. Epub 2021 Mar 1.