title: Reprogramming carcinoma associated fibroblasts by AC1MMYR2 impedes tumor metastasis and improves chemotherapy efficacy.
abstract: Carcinoma associated fibroblasts (CAFs) produce a nutrient-rich microenvironment to fuel tumor progression and metastasis. Reactive oxygen species (ROS) levels and the inflammation pathway co-operate to transform CAFs. Therefore, elucidating the mechanism mediating the activity of CAFs might identify novel therapies. Abnormal miR-21 expression was reported to be involved in the conversion of resident fibroblasts to CAFs, yet the factor that drives transformation was poorly understood. Here, we reported that high miR-21 expression was strongly associated with lymph node metastasis in breast cancer, and the activation of the miR-21/NF-кB was required for the metastatic promoting effect of CAFs. AC1MMYR2, a small molecule inhibitor of miR-21, attenuated NF-кB activity by directly targeting VHL, thereby blocking the co-precipitation of NF-кB and ß-catenin and nuclear translocation. Taxol failed to constrain the aggressive behavior of cancer cells stimulated by CAFs, whereas AC1MMYR2 plus taxol significantly suppressed tumor migration and invasion ability. Remodeling and depolarization of F-actin, decreased levels of β-catenin and vimentin, and increased E-cadherin were also detected in the combination therapy. Furthermore, reduced levels of FAP-α and α-SMA were observed, suggesting that AC1MMYR2 was competent to reprogram CAFs via the NF-кB/miR-21/VHL axis. Strikingly, a significant reduction of tumor growth and lung metastasis was observed in the combination treated mice. Taken together, our findings identified miR-21 as a critical mediator of metastasis in breast cancer through the tumor environment. AC1MMYR2 may be translated into the clinic and developed as a more personalized and effective neoadjuvant treatment for patients to reduce metastasis and improve the chemotherapy response.
authors.affiliation: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Head and Neck, Tianjin Cancer Institute and Hospital, Tianjin 300060, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Huan-Huan
authors.initials: HH
authors.lastname: Jia
authors.affiliation: Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, Tianjin 300052, China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, China.
authors.forename: Qi-Xue
authors.initials: QX
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Song
authors.affiliation: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Zhi-Yan
authors.initials: ZY
authors.lastname: Zhu
authors.affiliation: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Sun
authors.affiliation: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Hong-Xiao
authors.initials: HX
authors.lastname: Jiao
authors.affiliation: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Tian
authors.affiliation: Department of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Yu-Qi
authors.initials: YQ
authors.lastname: Yang
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Xiu-Lan
authors.initials: XL
authors.lastname: Zhao
authors.affiliation: Department of Head and Neck, Tianjin Cancer Institute and Hospital, Tianjin 300060, China.
authors.forename: Lun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China. Electronic address: mei_10668@163.com.
authors.forename: Mei
authors.initials: M
authors.lastname: Mei
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, China. Electronic address: kang97061@tmu.edu.cn.
authors.forename: Chun-Sheng
authors.initials: CS
authors.lastname: Kang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D002450:Cell Communication / Q000187:drug effects*; D045744:Cell Line, Tumor; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D011743:Pyrimidines / Q000494:pharmacology*; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: C584580:AC1MMYR2 compound; D000970:Antineoplastic Agents; D011743:Pyrimidines
keywords: AC1MMYR2; Carcinoma associated fibroblasts; Metastasis; NF-кB; VHL