miR-125a-5p regulation increases phosphorylation of FAK that contributes to imatinib resistance in gastrointestinal stromal tumors

Wen Kuan Huang, Pinar Akçakaya, Anastasia Gangaev, Linkiat Lee, Katarina Zeljic, Praveensingh Hajeri, Erik Berglund, Mehran Ghaderi, Jan Åhlén, Robert Bränström, Catharina Larsson, Weng Onn Lui

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

The use of imatinib mesylate has greatly improved the clinical outcome for gastrointestinal stromal tumor (GIST) patients. However, imatinib resistance is still a major clinical challenge, and the molecular mechanisms are not fully understood. We have previously shown that miR-125a-5p and its mRNA target PTPN18 modulate imatinib response in GIST cells. Herein, we evaluated phosphorylated FAK (pFAK) as a candidate downstream target of PTPN18 and the possible association of this regulation with imatinib resistance in GIST. FAK and pFAK expressions were evaluated in GIST882 cells transfected with short hairpin RNA or short interfering RNA targeting PTPN18 or miR-125a-5p mimic, imatinib-resistant GIST882R subclones and clinical samples using Western blot analyses. FAK phosphorylation was blocked using the FAK inhibitor 14 (FAKi) and the effects on cell viability and apoptosis were evaluated using WST-1 assay and cleaved PARP expression. Clinical associations of FAK and pFAK expression with imatinib resistance, KIT mutation and patient outcome were assessed by Fisher's exact test or log-rank test. Over-expression of miR-125a-5p and silencing of PTPN18 increased pFAK, but not FAK, expression in GIST cells. Higher pFAK expression was observed in the GIST882R subclones with acquired imatinib resistance compared to their imatinib-sensitive parental cells. Treatment with FAKi in imatinib-resistant GIST882R cells reduced cell viability and increased apoptosis upon imatinib treatment. Additionally, FAKi could rescue the imatinib resistance effect mediated by miR-125a-5p over-expression. In clinical samples, high FAK and pFAK expressions were associated with KIT mutation status, and high FAK expression was also associated with metastasis in GIST. Higher pFAK was found in cases with shorter overall survival. Our findings highlight an important role for miR-125a-5p regulation and its downstream target pFAK for imatinib resistance in GIST. pFAK and FAK may have prognostic values in GIST.

Original languageEnglish (US)
Pages (from-to)287-296
Number of pages10
JournalExperimental Cell Research
Volume371
Issue number1
DOIs
StatePublished - Oct 1 2018
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by the Swedish Research Council , the Swedish Cancer Society , Cancer Research Funds of Radiumhemmet, Karolinska Institutet and Stockholm County Council . W-K.H. is supported by a doctoral fellowship from the Chang Gung Memorial Hospital, Taiwan .

Funding Information:
This study was supported by the Swedish Research Council, the Swedish Cancer Society, Cancer Research Funds of Radiumhemmet, Karolinska Institutet and Stockholm County Council. W-K.H. is supported by a doctoral fellowship from the Chang Gung Memorial Hospital, Taiwan.

Publisher Copyright:
© 2018 The Author(s)

Keywords

  • Gastrointestinal stromal tumor
  • Imatinib resistance
  • PTPN18
  • miR-125a-5p
  • pFAK

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