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The role of protein kinase-C theta in control of epithelial to mesenchymal transition and cancer stem cell formation.

ABSTRACT: The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) induces transition of the epithelial MCF-7 cell line to a mesenchymal phenotype. A subset of the resulting mesenchymal cells has surface markers characteristics of a cancer stem cell (CSC) population. We profiled the transcriptome changes associated with the epithelial to mesenchymal transition and those that occurred in the CSC subset. Using a siRNA knockdown strategy, we examined the extent to which these changes were dependent on the PKC family member, PKC-?. The importance of the cytoplasmic signaling role of this kinase is well established and in this study, we have shown by PKC-? ChIP-sequencing analysis that this kinase has a dual role with the ability to also associate with chromatin on a subset of PKC-? dependent genes. In the associated manuscript (Zafar et al., 2014 [5]) we presented evidence for the first time showing that this nuclear role of PKC-? is also important for gene induction and mesenchymal/CSC phenotype. Here we describe the analysis associated with the transcriptome and ChIP-seq data presented in Zafar et al. (2014) [5] and uploaded to NCBI Gene Expression Omnibus (GSE53335).

SUBMITTER: Zafar A

PROVIDER: S-EPMC4535743 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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The role of protein kinase-C theta in control of epithelial to mesenchymal transition and cancer stem cell formation.

Zafar Anjum A Hardy Kristine K Wu Fan F Li Jasmine J Rao Sudha S

Genomics data 20141114

The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) induces transition of the epithelial MCF-7 cell line to a mesenchymal phenotype. A subset of the resulting mesenchymal cells has surface markers characteristics of a cancer stem cell (CSC) population. We profiled the transcriptome changes associated with the epithelial to mesenchymal transition and those that occurred in the CSC subset. Using a siRNA knockdown strategy, we examined the extent to which these changes were d ...[more]

PMID: 26484144

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Project description:Tumor‑stroma interactions serve a crucial role in the development of colorectal cancer (CRC), in which secreted protein acidic and rich in cysteine (SPARC) has been implicated. Due to interactions between cancer and stromal cells [mesenchymal stem cells (MSCs)], SPARC gene expression is markedly upregulated in CRC cells. The present study investigated the role of SPARC in CRC development and its potential as a biomarker. Specifically, the present study examined the association between SPARC expression and clinicopathological characteristics in 42 cases of CRC. SPARC expression in cancer cells was associated with T grade, N grade (TNM classification), stage and poor prognosis. Furthermore, the area of fibroblast‑activating protein‑positive staining around the cancer cells was increased in SPARC‑positive compared with SPARC‑negative cases. Proliferation and wound healing assays in SPARC‑silenced KM12SM cells [short hairpin RNA SPARC (shSPARC)], the reduced SPARC expression of which was demonstrated by reverse transcription‑quantitative PCR, revealed that the proliferative and migratory capacity of shSPARC cells did not differ from that of wild‑type (WT) cells. However, it was markedly reduced when co‑cultured with MSCs. Furthermore, in vivo, immunohistological analysis and RNA sequencing were conducted in an orthotopic implanted mouse model. Tumor growth and lymph node metastasis were markedly suppressed in shSPARC‑transplanted tumors compared with WT‑transplanted tumors, with a more marked suppression observed following shSPARC co‑transplantation with MSCs. Immunohistological examination further revealed that the stromal reaction and epithelial‑mesenchymal transition (EMT) were markedly suppressed in tumors co‑transplanted with shSPARC and MSCs, and these results were consistent with RNA sequencing using RNA extracted from orthotopic tumors. Overall, these results suggested that SPARC expression in CRC cells is dependent on the interaction between cancer cells and stromal cells to induce EMT and promote stromal formation in the tumor microenvironment, suggesting its suitability as a novel target molecule for CRC treatment.

Dataset Information

The role of protein kinase-C theta in control of epithelial to mesenchymal transition and cancer stem cell formation.

Publications

The role of protein kinase-C theta in control of epithelial to mesenchymal transition and cancer stem cell formation.

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