Dataset Information

KLF4-Mediated Suppression of CD44 Signaling Negatively Impacts Pancreatic Cancer Stemness and Metastasis.

ABSTRACT: KLF4 and CD44 regulate cancer cell stemness, but their precise functions and roles in metastatic progression are not well understood. In this study, we used both inducible and genetic engineering approaches to assess whether the activities of these two factors intersect in pancreatic cancer. We found that genetic ablation of Klf4 in pancreatic cancer cells isolated from Klf4(flox/flox) mice drastically increased CD44 expression and promoted the acquisition of stem-like properties, whereas tetracycline-inducible expression of KLF4 suppressed these properties in vitro and in vivo Further mechanistic investigation revealed that KLF4 bound to the CD44 promoter to negatively regulate transcription and also the expression of the CD44 variant. Moreover, in human pancreatic ductal adenocarcinoma (PDAC) tissues, the expression patterns of KLF4 and CD44 were mutually exclusive, and this inverse relationship was particularly striking in human metastatic pancreatic tumors and in autochthonous mouse models of PDAC. Taken together, our findings demonstrate that KLF4 acts as a tumor suppressor in PDAC cells that restricts metastatic behaviors through direct negative regulation of CD44, providing support for the clinical investigation of therapeutic approaches focusing on targeted KLF4 activation in advanced tumors. Cancer Res; 76(8); 2419-31. ©2016 AACR.

SUBMITTER: Yan Y

PROVIDER: S-EPMC4876033 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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KLF4-Mediated Suppression of CD44 Signaling Negatively Impacts Pancreatic Cancer Stemness and Metastasis.

Yan Yongmin Y Li Zhiwei Z Kong Xiangyu X Jia Zhiliang Z Zuo Xiangsheng X Gagea Mihai M Huang Suyun S Wei Daoyan D Xie Keping K

Cancer research 20160215 8

KLF4 and CD44 regulate cancer cell stemness, but their precise functions and roles in metastatic progression are not well understood. In this study, we used both inducible and genetic engineering approaches to assess whether the activities of these two factors intersect in pancreatic cancer. We found that genetic ablation of Klf4 in pancreatic cancer cells isolated from Klf4(flox/flox) mice drastically increased CD44 expression and promoted the acquisition of stem-like properties, whereas tetrac ...[more]

PMID: 26880805

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Project description:Background & aimsTumor-microenvironment factors and cancer stem cells (CSCs) play a critical role in the aggressiveness of pancreatic cancer (PC). However, the degree to which tumor-microenvironment factors promote stemness remains unexplored. Here, we examined whether cancer-associated fibroblasts (CAFs) promote CSC features in PC.MethodsPC cells were treated long-term (30, 60, and 90 days) with conditioned media (CM)-derived from normal human fibroblasts (NFs) and CAFs. The stemness features of tumorsphere formation and stemness populations, along with CSCs markers, were analyzed using 2-dimensional and 3-dimensional sodium alginate bead-based co-culture models. Immunohistochemistry and immunofluorescence staining were performed for CSCs and fibroblast markers in autochthonous KrasG12D/+; Trp53R172H/+; Pdx1-Cre mice and human pancreatic tumors. Polymerase chain reaction array and gene knockdown were performed to identify the mechanism of stemness enrichment.ResultsLong-term treatment of PC cells with CAF-CM enriched stemness, as indicated by significantly higher CD44+, ALDH+, and AF+ populations in PC cells. Increased tumorsphere formation and elevated CSC, self-renewal, and drug-resistance markers in CAF-CM-treated PC cells were observed. In addition, CAFs co-cultured with PC cells in the 3-dimensional model showed a substantial increase in stemness features. CD44 and α-smooth muscle actin were positively correlated and their expressions progressively increased from the early to late stages of KrasG12D/+; Trp53R172H/+; Pdx1-Cre mouse and human pancreatic tumors. Osteopontin/secreted phosphoprotein 1 was identified as the top differentially overexpressed gene in CAF-CM-treated PC cells and knockdown of osteopontin/secreted phosphoprotein 1 significantly reduced stemness characteristics in CAF-CM-treated PC cells.ConclusionsOur data uncovered novel insight into the interplay between CAF and enrichment of stemness population through the osteopontin/secreted phosphoprotein 1-CD44 axis in PC.

Project description:Approximately 25% of colorectal cancer (CRC) patients will develop metastatic (m)CRC despite treatment interventions. In this setting, tumor cells are attracted to the epidermal growth factor receptor (EGFR) oncogene. Kirsten rat sarcoma (RAS) 2 viral oncogene homolog (KRAS) mutations were reported to drive CRC by promoting cancer progression in activating Wnt/β-catenin and RAS/extracellular signal-regulated kinase (ERK) pathways. In addition, KRAS is associated with almost 40% of patients who acquire resistance to EGFR inhibitors in mCRC. Multiple studies have demonstrated that cancer stem cells (CSCs) promote tumorigenesis, tumor growth, and resistance to therapy. One of the most common CSC prognostic markers widely reported in CRC is a cluster of differentiation 44 (CD44), which regulates matrix metalloproteinases 7/9 (MMP7/9) to promote tumor progression and metastasis; however, the molecular role of CD44 in CRC is still unclear. In invasive CRC, overexpression of MMP7 was reported in tumor cells compared to normal cells and plays a crucial function in CRC cetuximab and oxaliplatin resistance and distant metastasis. Here, we utilized a bioinformatics analysis and identified overexpression of KRAS/MMP7/CD44 oncogenic signatures in CRC tumor tissues compared to normal tissues. In addition, a high incidence of mutations in KRAS and CD44 were associated with some of the top tumorigenic oncogene's overexpression, which ultimately promoted a poor response to chemotherapy and resistance to some FDA-approved drugs. Based on these findings, we explored a computational approach to drug repurposing of the drug, sulfasalazine, and our in silico molecular docking revealed unique interactions of sulfasalazine with the KRAS/MMP7/CD44 oncogenes, resulting in high binding affinities compared to those of standard inhibitors. Our in vitro analysis demonstrated that sulfasalazine combined with cisplatin reduced cell viability, colony, and sphere formation in CRC cell lines. In addition, sulfasalazine alone and combined with cisplatin suppressed the expression of KRAS/MMP7/CD44 in DLD-1 and HCT116 cell lines. Thus, sulfasalazine is worthy of further investigation as an adjuvant agent for improving chemotherapeutic responses in CRC patients.

Dataset Information

KLF4-Mediated Suppression of CD44 Signaling Negatively Impacts Pancreatic Cancer Stemness and Metastasis.

Publications

KLF4-Mediated Suppression of CD44 Signaling Negatively Impacts Pancreatic Cancer Stemness and Metastasis.

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