Abstract
Cytokeratin 19 (KRT19) is a cytoplasmic intermediate filament protein, which is responsible for structural rigidity and multipurpose scaffolds. In several cancers, KRT19 is overexpressed and may play a crucial role in tumorigenic transformation. In our previous study, we revealed the role of KRT19 as signaling component which mediated Wnt/NOTCH crosstalk through NUMB transcription in breast cancer. Here, we investigated the function of KRT19 in cancer reprogramming and drug resistance in breast cancer cells. We found that expression of KRT19 was attenuated in several patients-derived breast cancer tissues and patients with a low expression of KRT19 were significantly correlated with poor prognosis in breast cancer patients. Consistently, highly aggressive and drug-resistant breast cancer patient-derived cancer stem cell-like cells (konkuk university-cancer stem cell-like cell (KU-CSLCs)) displayed higher expression of cancer stem cell (CSC) markers, including ALDH1, CXCR4, and CD133, but a much lower expression of KRT19 than that is seen in highly aggressive triple negative breast cancer MDA-MB231 cells. Moreover, we revealed that the knockdown of KRT19 in MDA-MB231 cells led to an enhancement of cancer properties, such as cell proliferation, sphere formation, migration, and drug resistance, while the overexpression of KRT19 in KU-CSLCs resulted in the significant attenuation of cancer properties. KRT19 regulated cancer stem cell reprogramming by modulating the expression of cancer stem cell markers (ALDH1, CXCR4, and CD133), as well as the phosphorylation of Src and GSK3β (Tyr216). Therefore, our data may imply that the modulation of KRT19 expression could be involved in cancer stem cell reprogramming and drug sensitivity, which might have clinical implications for cancer or cancer stem cell treatment.
Highlights
Heterogeneity at the cellular and molecular level is a prominent feature of most tumor types, including breast cancer [1]
Our reverse transcriptase polymerase chain reaction (RT-Polymerase Chain Reaction (PCR)) results showed that the expression of KRT19 was attenuated in breast cancer tissue (C) when compared to their normal (N) counterparts (Figure 1A, upper panel); the clinical characterization of breast cancer patients was overviewed in Figure 1A, lower panel
The KRT19 was significantly downregulated in ductal breast cancer tissue as compared to the normal tissue (Figure 1B, upper panel) [49], KRT19 expression was upregulated in other breast cancer studies (Oncomine)
Summary
Heterogeneity at the cellular and molecular level is a prominent feature of most tumor types, including breast cancer [1]. In 2006, Takahashi and Yamanaka showed for the first time that pluripotent stem (PS) cells could be generated from mouse embryonic fibroblasts by ectopic expression of transcription factors (TFs), called Yamanaka factors, such as OCT4, C-MYC, KLF4, and SOX2 [9] Beside these Yamanaka factors, currently, there are around 25 TFs that are reported to be expressed in SCs. Of them, most of the TFs are suppressed in normal somatic cells, but are abnormally expressed in cancer cells [10,11], suggesting that the ectopic expression of stemness marker genes may cause the generation of abnormal cancer stem cells (CSCs). CSCs are a subtype of cells that have the capacity to self-renew, produce a heterogeneous subset of cancer cells, and initiate tumor generation [29,30] These findings may suggest a possible relationship between embryonic stem cells (ESCs)/iPSC reprogramming and tumor generation
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