Bioengineered miRNA-1291 prodrug therapy in pancreatic cancer cells and patient-derived xenograft mouse models

Mei Juan Tu, Pui Yan Ho, Qian Yu Zhang, Chao Jian, Jing Xin Qiu, Edward Kim, Richard J Bold, Frank J. Gonzalez, Huichang Bi, Aiming Yu

Research output: Contribution to journalArticle

Abstract

Our recent studies have revealed that microRNA-1291 (miR-1291) is downregulated in pancreatic cancer (PC) specimens and restoration of miR-1291 inhibits tumorigenesis of PC cells. This study is to assess the efficacy and underlying mechanism of our bioengineered miR-1291 prodrug monotherapy and combined treatment with chemotherapy. AT-rich interacting domain protein 3B (ARID3B) was verified as a new target for miR-1291, and miR-1291 prodrug was processed to mature miR-1291 in PC cells which surprisingly upregulated ARID3B mRNA and protein levels. Co-administration of miR-1291 with gemcitabine plus nab-paclitaxel (Gem-nP) largely increased the levels of apoptosis, DNA damage and mitotic arrest in PC cells, compared to mono-drug treatment. Consequently, miR-1291 prodrug improved cell sensitivity to Gem-nP. Furthermore, systemic administration of in vivo-jetPEI-formulated miR-1291 prodrug suppressed tumor growth in both PANC-1 xenograft and PC patients derived xenograft (PDX) mouse models to comparable degrees as Gem-nP alone, while combination treatment reduced tumor growth more ubiquitously and to the greatest degrees (70–90%), compared to monotherapy. All treatments were well tolerated in mice. In conclusion, biologic miR-1291 prodrug has therapeutic potential as a monotherapy for PC, and a sensitizing agent to chemotherapy.

LanguageEnglish (US)
Pages82-90
Number of pages9
JournalCancer Letters
Volume442
DOIs
StatePublished - Feb 1 2019

Fingerprint

Prodrugs
MicroRNAs
Pancreatic Neoplasms
Heterografts
gemcitabine
Therapeutics
Drug Therapy
Growth
DNA Damage
Neoplasms
Carcinogenesis
Down-Regulation
Apoptosis
Messenger RNA

Keywords

  • ARID3B
  • Gemcitabine plus nab-paclitaxel
  • miR-1291
  • Pancreatic cancer
  • PDX model

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Bioengineered miRNA-1291 prodrug therapy in pancreatic cancer cells and patient-derived xenograft mouse models. / Tu, Mei Juan; Ho, Pui Yan; Zhang, Qian Yu; Jian, Chao; Qiu, Jing Xin; Kim, Edward; Bold, Richard J; Gonzalez, Frank J.; Bi, Huichang; Yu, Aiming.

In: Cancer Letters, Vol. 442, 01.02.2019, p. 82-90.

Research output: Contribution to journalArticle

Tu, Mei Juan ; Ho, Pui Yan ; Zhang, Qian Yu ; Jian, Chao ; Qiu, Jing Xin ; Kim, Edward ; Bold, Richard J ; Gonzalez, Frank J. ; Bi, Huichang ; Yu, Aiming. / Bioengineered miRNA-1291 prodrug therapy in pancreatic cancer cells and patient-derived xenograft mouse models. In: Cancer Letters. 2019 ; Vol. 442. pp. 82-90.
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