Antitumor and off-target effects of cholesterol-conjugated let-7a mimics in an orthotopic hepatocellular carcinoma xenograft nude mouse model
Objective:. To explore the antitumor and potential off-target effects of systemically delivered cholesterol-conjugated let-7a mimics (Chol-let-7a) and control mimics (Chol-miRCtrl) on hepatocellular carcinoma in vivo. Methods:. The antitumor effects of two intravenous dosing regimens of Chol-let-7a...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wolters Kluwer Health
2022-12-01
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| Series: | Journal of Bio-X Research |
| Online Access: | http://journals.lww.com/10.1097/JBR.0000000000000103 |
| _version_ | 1797947114027745280 |
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| author | Jian Guan Mingyang Liu Xin Li Liangrui Zhou Xueyu Dong Wei Dai Yu Xia Tao Yang Shaojuan Guo Xingqi Li Yehua Han Yufeng Luo |
| author_facet | Jian Guan Mingyang Liu Xin Li Liangrui Zhou Xueyu Dong Wei Dai Yu Xia Tao Yang Shaojuan Guo Xingqi Li Yehua Han Yufeng Luo |
| author_sort | Jian Guan |
| collection | DOAJ |
| description | Objective:. To explore the antitumor and potential off-target effects of systemically delivered cholesterol-conjugated let-7a mimics (Chol-let-7a) and control mimics (Chol-miRCtrl) on hepatocellular carcinoma in vivo.
Methods:. The antitumor effects of two intravenous dosing regimens of Chol-let-7a on heptocellular carcinoma growth were compared using an orthotopic xenograft mouse model. Off-targets were analyzed with histopathological and ultrapathological features of heparenal tissue and cells in the Chol-let-7a-, Chol-miRCtrl-, and saline-treated (blank) xenograft mice and normal control mice. Then, let-7a abundance in orthotopic tumors, corresponding paracancerous hepatic tissue, and normal liver tissue from healthy nude mice was examined by reverse transcription-polymerase chain reaction. The distribution of Chol-let-7a and Chol-miRCtrl in vivo was examined by whole-animal imaging and frozen-sections observation. The experiments were approved by the Institutional Research Board of Peking Union Medical College Hospital.
Results:. Continuous treatment with Chol-let-7a resulted in tumors that were 35.86% and 40.02% the size of those in the Chol-miRCtrl and blank xenograft group (P < 0.01 and P < 0.01, respectively), while intermittent dosing with Chol-let-7a resulted in tumors that were 65.42% and 56.66% the size of those in the Chol-miRCtrl and the blank control group, respectively (P < 0.05 and P < 0.05). In addition, some histopathological and ultrapathological features were only observed after treatment with the two cholesterol-conjugated molecules, however mild with intermittent dosing Chol-let-7a treatment, such as diffuse sinusoidal dilation and edema, primarily around the centrolobular vein in heptic tissues; mild hypercellularity with dilated capillary lumens in the renal tissue; and some organelle abnormalities found in heptic and renal cells. Furthermore, whole-animal imaging showed that Chol-let-7a and Chol-miRCtrl were predominantly distributed in the liver, kidney, and bladder regions after injection, and that the concentration of Chol-let-7a and Chol-miRCtrl in the kidney and the bladder decreased much slowly in the xenograft animals, especially in the Chol-miRCtrl group. Finally, RT-PCR analysis showed that let-7a levels were significantly increased in Chol-let-7a-treated xenografts compared with Chol-miRCtrl group (P=0.003) and blank xenograft group (P=0.001); however, the level was only equivalent to 50.6% and 40.7% of that in paracancerous hepatic tissue and hepatic tissue in normal mice, respectively.
Conclusions:. Chol-let-7a, administered either continuously or intermittently, showed effective antitumor efficacy. Chol-let-7a had some off-target effects, such as mild acute hepatitis-like inflammation and non-specific drug-induced kidney injury. The intermittent dosing regimen resulted in less damage than the continuous regimen, while maintaining relatively satisfactory antitumor efficacy, which could be useful for the investigation and possible clinical use of miRNA treatment regimens in the future. |
| first_indexed | 2024-04-10T21:21:37Z |
| format | Article |
| id | doaj.art-50261826130141d393c957e6a997f2b3 |
| institution | Directory Open Access Journal |
| issn | 2096-5672 |
| language | English |
| last_indexed | 2024-04-10T21:21:37Z |
| publishDate | 2022-12-01 |
| publisher | Wolters Kluwer Health |
| record_format | Article |
| series | Journal of Bio-X Research |
| spelling | doaj.art-50261826130141d393c957e6a997f2b32023-01-20T02:41:35ZengWolters Kluwer HealthJournal of Bio-X Research2096-56722022-12-015418119610.1097/JBR.0000000000000103202212000-00006Antitumor and off-target effects of cholesterol-conjugated let-7a mimics in an orthotopic hepatocellular carcinoma xenograft nude mouse modelJian Guan0Mingyang Liu1Xin Li2Liangrui Zhou3Xueyu Dong4Wei Dai5Yu Xia6Tao Yang7Shaojuan Guo8Xingqi Li9Yehua Han10Yufeng Luo11a The National Population and Health Scientific Data Centre (Clinical Medicine)b Department of Pathologyc Department of Nuclear Medicine, Peking Union Medical College Hosptial, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijingb Department of Pathologye National Laboratory of Medical Biology, Institute of Basic Medical Sciencesf The Electron Microscope Laboratories Center, Institute of Basic Medical Sciencesg Department of Ultrasound, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, Chinaa The National Population and Health Scientific Data Centre (Clinical Medicine)a The National Population and Health Scientific Data Centre (Clinical Medicine)b Department of Pathologyf The Electron Microscope Laboratories Center, Institute of Basic Medical Sciencesb Department of PathologyObjective:. To explore the antitumor and potential off-target effects of systemically delivered cholesterol-conjugated let-7a mimics (Chol-let-7a) and control mimics (Chol-miRCtrl) on hepatocellular carcinoma in vivo. Methods:. The antitumor effects of two intravenous dosing regimens of Chol-let-7a on heptocellular carcinoma growth were compared using an orthotopic xenograft mouse model. Off-targets were analyzed with histopathological and ultrapathological features of heparenal tissue and cells in the Chol-let-7a-, Chol-miRCtrl-, and saline-treated (blank) xenograft mice and normal control mice. Then, let-7a abundance in orthotopic tumors, corresponding paracancerous hepatic tissue, and normal liver tissue from healthy nude mice was examined by reverse transcription-polymerase chain reaction. The distribution of Chol-let-7a and Chol-miRCtrl in vivo was examined by whole-animal imaging and frozen-sections observation. The experiments were approved by the Institutional Research Board of Peking Union Medical College Hospital. Results:. Continuous treatment with Chol-let-7a resulted in tumors that were 35.86% and 40.02% the size of those in the Chol-miRCtrl and blank xenograft group (P < 0.01 and P < 0.01, respectively), while intermittent dosing with Chol-let-7a resulted in tumors that were 65.42% and 56.66% the size of those in the Chol-miRCtrl and the blank control group, respectively (P < 0.05 and P < 0.05). In addition, some histopathological and ultrapathological features were only observed after treatment with the two cholesterol-conjugated molecules, however mild with intermittent dosing Chol-let-7a treatment, such as diffuse sinusoidal dilation and edema, primarily around the centrolobular vein in heptic tissues; mild hypercellularity with dilated capillary lumens in the renal tissue; and some organelle abnormalities found in heptic and renal cells. Furthermore, whole-animal imaging showed that Chol-let-7a and Chol-miRCtrl were predominantly distributed in the liver, kidney, and bladder regions after injection, and that the concentration of Chol-let-7a and Chol-miRCtrl in the kidney and the bladder decreased much slowly in the xenograft animals, especially in the Chol-miRCtrl group. Finally, RT-PCR analysis showed that let-7a levels were significantly increased in Chol-let-7a-treated xenografts compared with Chol-miRCtrl group (P=0.003) and blank xenograft group (P=0.001); however, the level was only equivalent to 50.6% and 40.7% of that in paracancerous hepatic tissue and hepatic tissue in normal mice, respectively. Conclusions:. Chol-let-7a, administered either continuously or intermittently, showed effective antitumor efficacy. Chol-let-7a had some off-target effects, such as mild acute hepatitis-like inflammation and non-specific drug-induced kidney injury. The intermittent dosing regimen resulted in less damage than the continuous regimen, while maintaining relatively satisfactory antitumor efficacy, which could be useful for the investigation and possible clinical use of miRNA treatment regimens in the future.http://journals.lww.com/10.1097/JBR.0000000000000103 |
| spellingShingle | Jian Guan Mingyang Liu Xin Li Liangrui Zhou Xueyu Dong Wei Dai Yu Xia Tao Yang Shaojuan Guo Xingqi Li Yehua Han Yufeng Luo Antitumor and off-target effects of cholesterol-conjugated let-7a mimics in an orthotopic hepatocellular carcinoma xenograft nude mouse model Journal of Bio-X Research |
| title | Antitumor and off-target effects of cholesterol-conjugated let-7a mimics in an orthotopic hepatocellular carcinoma xenograft nude mouse model |
| title_full | Antitumor and off-target effects of cholesterol-conjugated let-7a mimics in an orthotopic hepatocellular carcinoma xenograft nude mouse model |
| title_fullStr | Antitumor and off-target effects of cholesterol-conjugated let-7a mimics in an orthotopic hepatocellular carcinoma xenograft nude mouse model |
| title_full_unstemmed | Antitumor and off-target effects of cholesterol-conjugated let-7a mimics in an orthotopic hepatocellular carcinoma xenograft nude mouse model |
| title_short | Antitumor and off-target effects of cholesterol-conjugated let-7a mimics in an orthotopic hepatocellular carcinoma xenograft nude mouse model |
| title_sort | antitumor and off target effects of cholesterol conjugated let 7a mimics in an orthotopic hepatocellular carcinoma xenograft nude mouse model |
| url | http://journals.lww.com/10.1097/JBR.0000000000000103 |
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