Bioengineered Let-7c Inhibits Orthotopic Hepatocellular Carcinoma and Improves Overall Survival with Minimal Immunogenicity

Joseph L. Jilek, Qian Yu Zhang, Mei Juan Tu, Pui Yan Ho, Zhijian Duan, Jing Xin Qiu, Aiming Yu

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths, warranting better therapies. Restoration of tumor-suppressive microRNAs depleted in hepatocellular carcinoma represents a new therapeutic strategy. Herein, we sought to identify a potent microRNA (miRNA) agent that could alleviate HCC tumor burden and improve survival. Among a collection of bioengineered noncoding RNA molecules produced through bacterial fermentation, we identified let-7c agent as the most potent inhibitor of HCC cell viability. Bioengineered let-7c selectively modulated target gene expression (Lin-28 homolog B [LIN28B], AT-rich interactive domain-containing protein 3B [ARID3B], B cell lymphoma-extra large [Bcl-xl], and c-Myc) in HCC cells, and consequently induced apoptosis and inhibited tumorsphere growth. When formulated with liposomal-branched polyethylenimine polyplex, bioengineered let-7c exhibited serum stability up to 24 h. Furthermore, liposomal polyplex-formulated let-7c could effectively reduce tumor burden and progression in orthotopic HCC mouse models, while linear polyethyleneimine-formulated let-7c to a lower degree, as revealed by live animal and ex vivo tissue imaging studies. This was also supported by reduced serum α-fetoprotein and bilirubin levels in let-7c-treated mice. In addition, lipopolyplex-formulated let-7c extended overall survival of HCC tumor-bearing mice and elicited no or minimal immune responses in healthy immunocompetent mice and human peripheral blood mononuclear cells. These results demonstrate that bioengineered let-7c is a promising molecule for advanced HCC therapy, and liposomal polyplex is a superior modality for in vivo RNA delivery.

Original languageEnglish (US)
Pages (from-to)498-508
Number of pages11
JournalMolecular Therapy - Nucleic Acids
Volume14
DOIs
StatePublished - Mar 1 2019

Fingerprint

Hepatocellular Carcinoma
Survival
Polyethyleneimine
Tumor Burden
MicroRNAs
Fetal Proteins
Neoplasms
Untranslated RNA
B-Cell Lymphoma
Serum
Bilirubin
Fermentation
Linear Models
Blood Cells
Cell Survival
Therapeutics
RNA
Apoptosis
Gene Expression
Growth

Keywords

  • bioengineering
  • hepatocellular carcinoma
  • lipopolyplex
  • microRNA
  • xenograft

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Bioengineered Let-7c Inhibits Orthotopic Hepatocellular Carcinoma and Improves Overall Survival with Minimal Immunogenicity. / Jilek, Joseph L.; Zhang, Qian Yu; Tu, Mei Juan; Ho, Pui Yan; Duan, Zhijian; Qiu, Jing Xin; Yu, Aiming.

In: Molecular Therapy - Nucleic Acids, Vol. 14, 01.03.2019, p. 498-508.

Research output: Contribution to journalArticle

Jilek, Joseph L. ; Zhang, Qian Yu ; Tu, Mei Juan ; Ho, Pui Yan ; Duan, Zhijian ; Qiu, Jing Xin ; Yu, Aiming. / Bioengineered Let-7c Inhibits Orthotopic Hepatocellular Carcinoma and Improves Overall Survival with Minimal Immunogenicity. In: Molecular Therapy - Nucleic Acids. 2019 ; Vol. 14. pp. 498-508.
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