Cancer Research and Treatment

Original Articles

Studying the Effect of Downregulating Autophagy-Related Gene LC3 on TLR3 Apoptotic Pathway Mediated by dsRNA in Hepatocellular Carcinoma Cells: Guilan Wang, Maona Zhang, Yunlong Li, Jiaming Zhou, Li Chen; Cancer Res Treat. 2017;49(1):230-245. Published online June 13, 2016; DOI: https://doi.org/10.4143/crt.2015.506

Purpose
The purpose of this study is to examine the role of the double-stranded RNA (dsRNA) activated Toll–interleukin-1 receptor domain-containing adaptor inducing interferon β (TRIF) signal pathway in triggering apoptosis in hepatocellular carcinoma (HCC) cells.
Materials and Methods
First, siRNA targeted autophagy–related gene LC3 (pU6H1-LC3 siRNA and siLC3) and a dsRNA used as a Toll-like receptor 3 (TLR3) ligand was constructed and synthesized, respectively. Then, a human HCC cell line was transfected with dsRNA, siLC3, and cotransfected with siLC3 and dsRNA (siLC3+dsRNA), respectively. Finally, quantification real-time polymerase chain reaction, western blotting, and immunofluorescence staining were used in the HCC line (SMMC7721), and MTT assay, flow cytometry, terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling, and transmission electron microscopy were used in an HCC xenograft model of nude mice. Human umbilical vein endothelial cell tube forming assay, color Doppler ultrasonographic flow image examination, and CD34-positive microvessel density were used in vitro and in vivo.
Results
Compared with untreated cells, the protein and mRNA expression of TLR3 and TRIF was up-regulated, in order, siLC3+dsRNA, dsRNA, and siLC3. Expression of LC3 was obviously down-regulated and the autophagosomes were significantly decreased in siLC3+dsRNA and siLC3, whereas in dsRNA (p < 0.05). LC3 and TRIF colocation was observed in HepG2 cells. Decreased cell viability, increased apoptosis, decrease in xenograft tumor volume, and angiogenesis potential were also observed in order (p < 0.05).
Conclusion
Suppression of intracellular autophagy resulted in decreased degradation of TRIF protein, which can promote triggering of apoptosis by the TLR3-TRIF pathway. dsRNA and siLC3 could play anticancer roles in coordination.

Citations

Citations to this article as recorded by

A Multi-Omics Analysis of a Mitophagy-Related Signature in Pan-Cancer
Nora Agir, Ilias Georgakopoulos-Soares, Apostolos Zaravinos
International Journal of Molecular Sciences.2025; 26(2): 448. CrossRef
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Bin Han, Chao Zhang, Xiaoxiao Wang, Huangqin Song, Lei Zhang, Tao Li, Jiefeng He, Haoliang Zhao
Frontiers in Bioscience-Landmark.2023;[Epub] CrossRef
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Up-regulation of miR-146a increases the sensitivity of non-small cell lung cancer to DDP by downregulating cyclin J
Lin Shi, Zhaozhong Xu, Gang Wu, Xiaoting Chen, Yuanyuan Huang, Yanjing Wang, Weiqiang Jiang, Bin Ke
BMC Cancer.2017;[Epub] CrossRef

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Blockade of Autophagy Aggravates Endoplasmic Reticulum Stress and Improves Paclitaxel Cytotoxicity in Human Cervical Cancer Cells: Li Xu, Jing-Hua Liu, Jing Zhang, Na Zhang, Zan-Hong Wang; Cancer Res Treat. 2015;47(2):313-321. Published online September 11, 2014; DOI: https://doi.org/10.4143/crt.2013.222

Abstract PDF PubReader ePub

Purpose
Autophagy is one of the ways to degrade unfolded proteins after endoplasmic reticulum (ER) stress. The purpose of this study is to determine whether a blockade of autophagy leads to aggravated endoplasmic reticulum stress, which then induces cells apoptosis in HeLa cells treated with paclitaxel.
Materials and Methods
Autophagy activation and the proapoptotic effects were characterized using monodansylcadaverine labeling and Hoechest staining, respectively. A Western blot analysis was used to detect the expression of apoptotic and autophagy-related genes. A flow cytometry was used to assess the cell apoptosis ratio.
Results
Paclitaxel exposure induced the aggregation of autophagosomes in the cytoplasms of cervical cancer HeLa cells. The expression of Beclin 1 and LC3 II were upregulated, but p62 was downregulated, which suggests that autophagy was promoted by paclitaxel. On the other hand, the expression of GRP78 obviously increased, suggesting that ER stress was induced after paclitaxel treatment. The cell proliferation assay indicated that a knockdown of Beclin 1 sensitized HeLa cells to paclitaxel. Furthermore, paclitaxel-mediated apoptotic cell death was further potentiated by the pretreatment with autophagy inhibitor chloroquine or small interfering RNA against Beclin 1. These results suggest that an induction of autophagy by paclitaxel may induce cell survival rather than cell death in HeLa cells; moreover, inhibition of autophagy led to an aggravated ER stress and an induction of downstream apoptosis.
Conclusion
Our results reveal autophagy induced by paclitaxel conferred protection of tumor cells against apoptosis, and blockade of autophagy subsequently aggravated ER stress, enhancing the apoptosis associated with paclitaxel treatment in HeLa cells.

Citations

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Journal of Drug Delivery Science and Technology.2022; 73: 103457. CrossRef
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Oncogene.2020; 39(43): 6704. CrossRef
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Polina V. Shnaider, Olga M. Ivanova, Irina K. Malyants, Ksenia S. Anufrieva, Ilya A. Semenov, Marat S. Pavlyukov, Maria A. Lagarkova, Vadim M. Govorun, Victoria O. Shender
International Journal of Molecular Sciences.2020; 21(21): 7872. CrossRef
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Biochemical and Biophysical Research Communications.2019; 513(1): 234. CrossRef
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Wen Wang, Shujuan Yao, Hongjing Jiang, Jing Dong, Xiujuan Cui, Xiangyu Tian, Yanyan Guo, Shiqian Zhang
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Anti-Cancer Drugs.2017; 28(3): 307. CrossRef
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International Journal of Molecular Sciences.2017; 18(4): 792. CrossRef
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Xiaobing Wang, Xiufang Liu, Yixiang Li, Pan Wang, Xiaolan Feng, Quanhong Liu, Fei Yan, Hairong Zheng
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