1. Academic Validation
  2. STAT3 exacerbates survival of cancer stem-like tumorspheres in EGFR-positive colorectal cancers: RNAseq analysis and therapeutic screening

STAT3 exacerbates survival of cancer stem-like tumorspheres in EGFR-positive colorectal cancers: RNAseq analysis and therapeutic screening

  • J Biomed Sci. 2018 Aug 2;25(1):60. doi: 10.1186/s12929-018-0456-y.
Chun-Chia Cheng 1 2 Po-Nien Liao 1 2 Ai-Sheng Ho 3 Ken-Hong Lim 1 2 4 Jungshan Chang 5 Ying-Wen Su 1 2 4 Caleb Gon-Shen Chen 1 2 4 Ya-Wen Chiang 1 2 Bi-Ling Yang 3 Huan-Chau Lin 1 2 Yu-Cheng Chang 1 2 Chun-Chao Chang 6 7 Yi-Fang Chang 8 9 10
Affiliations

Affiliations

  • 1 Division of Hematology and Oncology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan.
  • 2 Laboratory of Good Clinical Research Center, Department of Medical Research, Mackay Memorial Hospital, Tamsui District, New Taipei City, Taiwan.
  • 3 Division of Gastroenterology, Cheng Hsin General Hospital, Taipei, Taiwan.
  • 4 Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.
  • 5 Graduate Institute of Medical Sciences, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 6 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan. [email protected]
  • 7 Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. [email protected]
  • 8 Division of Hematology and Oncology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan. [email protected]
  • 9 Laboratory of Good Clinical Research Center, Department of Medical Research, Mackay Memorial Hospital, Tamsui District, New Taipei City, Taiwan. [email protected]
  • 10 Department of Medicine, MacKay Medical College, New Taipei City, Taiwan. [email protected]
Abstract

Background: Cancer Stem Cells are capable of undergoing cell division after surviving Cancer therapies, leading to tumor progression and recurrence. Inhibitory agents against Cancer Stem Cells may be therapeutically used for efficiently eradicating tumors. Therefore, the aim of this study was to identify the relevant driver genes that maintain Cancer stemness in epidermal growth factor receptor (EGFR)-positive colorectal Cancer (CRC) cells and to discover effective therapeutic agents against these genes.

Methods: In this study, EGFR-positive Cancer stem-like cells (CSLCs) derived from HCT116 and HT29 cells were used as study models for in vitro inductions. To identify the differential genes that maintain CSLCs, RNAseq analysis was conducted followed by bioinformatics analysis. Moreover, a panel containing 172 therapeutic agents targeting the various pathways of stem cells was used to identify effective therapeutics against CSLCs.

Results: RNAseq analysis revealed that 654 and 840 genes were significantly upregulated and downregulated, respectively, in the HCT116 CSLCs. Among these genes, notably, platelet-derived growth factor A (PDGFA) and signal transducer and activator of transcription 3 (STAT3) were relevant according to the Cancer pathway analyzed using NetworkAnalyst. Furthermore, therapeutic screening revealed that the agents targeting STAT3 and Wnt signaling pathways were efficient in reducing the cell viabilities of both HCT116 and HT29 cells. Consequently, we discovered that STAT3 inhibition using homoharringtonine and STAT3 knockdown significantly reduced the formation and survival of HT29-derived tumorspheres. We also observed that STAT3 phosphorylation was regulated by epidermal growth factor (EGF) to induce PDGFA and Wnt signaling cascades.

Conclusions: We identified the potential genes involved in tumorsphere formation and survival in selective EGFR-positive CRCs. The results reveal that the EGF-STAT3 signaling pathway promotes and maintains CRC stemness. In addition, a crosstalk between STAT3 and Wnt activates the Wnt/β-catenin signaling pathway, which is also responsible for Cancer stemness. Thus, STAT3 is a putative therapeutic target for CRC treatment.

Keywords

Cancer stem cell; EGFR; LGR5; PDGFA; STAT3; Wnt.

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