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Targeting LncRNA LLNLR-299G3.1 with antisense oligonucleotide inhibits malignancy of esophageal squamous cell carcinoma cells in vitro and in vivo

LI TIAN1,#, YONGYI HUANG1,#, BAOZHEN ZHANG2,#, YI SONG1,#, LIN YANG3, QIANQIAN CHEN1, ZHENG WANG3, YILING WANG1, QIHAN HE1, WENHAN YANG1, SHUYONG YU4, TIANYU LU5, ZICHEN LIU1, KAIPING GAO1,*, XIUJUN FAN2,*, JIAN SONG4,*, RIHONG ZHAI1,*

1 School of Public Health, International Cancer Center, Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen University Medical School, Shenzhen, China
2 Shenzhen Institute of Advanced Technology, Chinese Academy of Science, Shenzhen, China
3 Department of Thoracic Surgery, Shenzhen People’s Hospital, Shenzhen, China
4 Department of Gastroenterology, Hainan Tumor Hospital, Haikou, China
5 Department of Gastroenterology, Southern University of Science and Technology Hospital, Shenzhen, China

* Corresponding Authors: KAIPING GAO. Email: email; XIUJUN FAN. Email: email; JIAN SONG. Email: email; RIHONG ZHAI. Email: email

Oncology Research 2023, 31(4), 463-479. https://doi.org/10.32604/or.2023.028791

Abstract

Accumulating evidence has indicated that long non-coding RNAs (lncRNAs) play critical roles in the development and progression of cancers, including esophageal squamous cell carcinoma (ESCC). However, the mechanisms of lncRNAs in ESCC are still incompletely understood and therapeutic attempts for in vivo targeting cancer-associated lncRNA remain a challenge. By RNA-sequencing analysis, we identified that LLNLR-299G3.1 was a novel ESCC-associated lncRNA. LLNLR-299G3.1 was up-regulated in ESCC tissues and cells and promoted ESCC cell proliferation and invasion. Silencing of LLNLR-299G3.1 with ASO (antisense oligonucleotide) resulted in opposite effects. Mechanistically, LLNLR-299G3.1 bound to cancer-associated RNA binding proteins and regulated the expression of cancer-related genes, including OSM, TNFRSF4, HRH3, and SSTR3. ChIRP-seq (chromatin isolation by RNA purification and sequencing) revealed that these genes contained enriched chromatin binding sites for LLNLR-299G3.1. Rescue experiments confirmed that the effects of LLNLR-299G3.1 on ESCC cell proliferation were dependent on interaction with HRH3 and TNFRSF4. Therapeutically, intravenous delivery of placental chondroitin sulfate A binding peptide-coated nanoparticles containing antisense oligonucleotide (pICSA-BP-ANPs) strongly inhibited ESCC tumor growth and significantly improved animal survival in vivo. Overall, our results suggest that LLNLR-299G3.1 promotes ESCC malignancy through regulating gene-chromatin interactions and targeting ESCC by pICSA-BP-ANPs may be an effective strategy for the treatment of lncRNA-associated ESCC.

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Cite This Article

TIAN, L., HUANG, Y., ZHANG, B., SONG, Y., YANG, L. et al. (2023). Targeting LncRNA LLNLR-299G3.1 with antisense oligonucleotide inhibits malignancy of esophageal squamous cell carcinoma cells in vitro and in vivo. Oncology Research, 31(4), 463–479.



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