Xu Yang1, GuiXia Wu2, Qin Zhang3, Xia Chen3, Juan Li3, Qian Han3, Lei Yang3, Chendi Wang3, Mei Huang3, Yun Li3, Jiao Chen3, Haiying Wang3, Kaijiang Liu4. 1. Department of Obstetrics and Gynecology, The Fifth Affiliated People's Hospital of Chengdu University of Traditional Chinese Medicine, No. 33, Mashi Street, Wenjiang District, Chengdu, 610000, Sichuan, People's Republic of China. zhizihuakai@cdutcm.edu.cn. 2. Department of Physiology, School of Basic Medicine, Xinjiang Medical University, Urumchi, Xinjiang Uygur Autonomous Region, People's Republic of China. 3. Department of Obstetrics and Gynecology, The Fifth Affiliated People's Hospital of Chengdu University of Traditional Chinese Medicine, No. 33, Mashi Street, Wenjiang District, Chengdu, 610000, Sichuan, People's Republic of China. 4. Department of Gynecological Oncology, Ren Ji Hospital, School of Medicine, Shanghai JiaoTong University, No145 Middle Shandong Road, Huangpu District, Shanghai, 200001, People's Republic of China. liukaijiang@263.net.
Abstract
PURPOSE: Ovarian carcinoma is the fifth commonest malignancy in females and exhibits a high recurrence rate. High-grade serous ovarian carcinoma (HGSOC) is the main histologic subtype. It displays extensive genetic heterogeneity. Here, we aimed to identify potential therapeutic targets for HGSOC. METHODS: Both bioinformatic data from TCGA and 73 pairs of tumor and normal samples from patients were analyzed to reveal the expression level of ACSM3 in HGSOC. Next, cellular and animal experiments, including cell proliferation, colony formation and xenograft assays were performed to explore the suppressive function of ACSM3. Finally, biochemical methods, AMP/ATP ratio measurements and Western blotting were used to elucidate the mechanism underlying the ACSM3-AMPK axis in HGSOC. RESULTS: After analyzing transcriptome data of TCGA HGSOC samples, we found that ACSM3 is down-regulated in patient samples compared with normal controls. This observation was validated using data from primary clinical samples. Proliferation, soft agar colony formation and xenograft assays revealed that ACSM3 is able to suppress HGSOC tumor growth both in vitro and in vivo. Moreover, we found that ACSM3 overexpression increased the AMP/ATP ratio and the phosphorylation level of AMPK at threonine 172. In addition, we found that AMPK silencing in EFO21 and SKOV3 cells completely abolished the anti-oncogenic effect of ACSM3. CONCLUSION: Our data indicate that the ACSM3-AMPK axis is involved in the pathogenesis of HGSOC and, as such, may act as a therapeutic target for this cancer.
PURPOSE: Ovarian carcinoma is the fifth commonest malignancy in females and exhibits a high recurrence rate. High-grade serous ovarian carcinoma (HGSOC) is the main histologic subtype. It displays extensive genetic heterogeneity. Here, we aimed to identify potential therapeutic targets for HGSOC. METHODS: Both bioinformatic data from TCGA and 73 pairs of tumor and normal samples from patients were analyzed to reveal the expression level of ACSM3 in HGSOC. Next, cellular and animal experiments, including cell proliferation, colony formation and xenograft assays were performed to explore the suppressive function of ACSM3. Finally, biochemical methods, AMP/ATP ratio measurements and Western blotting were used to elucidate the mechanism underlying the ACSM3-AMPK axis in HGSOC. RESULTS: After analyzing transcriptome data of TCGA HGSOC samples, we found that ACSM3 is down-regulated in patient samples compared with normal controls. This observation was validated using data from primary clinical samples. Proliferation, soft agar colony formation and xenograft assays revealed that ACSM3 is able to suppress HGSOC tumor growth both in vitro and in vivo. Moreover, we found that ACSM3 overexpression increased the AMP/ATP ratio and the phosphorylation level of AMPK at threonine 172. In addition, we found that AMPK silencing in EFO21 and SKOV3 cells completely abolished the anti-oncogenic effect of ACSM3. CONCLUSION: Our data indicate that the ACSM3-AMPK axis is involved in the pathogenesis of HGSOC and, as such, may act as a therapeutic target for this cancer.
Authors: Jin Sun Lee; Ji Young Sul; Jun Beom Park; Myung Sun Lee; Eun Young Cha; Young Bok Ko Journal: Int J Mol Med Date: 2019-03-05 Impact factor: 4.101