Abstract
Highly tumorigenic stem-like cells, considered tumor-initiating cells (TICs), are the main cause of lung cancer initiation, relapse, and drug resistance. In this study, we identified that Ca2+/calmodulin-dependent protein kinase IIγ (CaMKIIγ) was aberrantly expressed in highly tumorigenic stem-like lung cancer cells, and was also correlated with poor prognosis in human lung cancer. Functionally, CaMKIIγ enhanced stem-like traits and the tumorigenicity of lung cancer cells in an Akt- and β-catenin-dependent manner. In addition, we found that CaMKIIγ upregulated Oct4 expression via Akt-mediated histone acetylation. Taken together, our findings reveal a critical role of CaMKIIγ in regulating the stemness and tumorigenicity of lung cancer cells and offer a promising therapeutic target for TICs.
Highlights
Phenotypic heterogeneity of cancer cells as a consequence of genetic change and environmental differences leads to formation of a tumor ecosystem composed of various cell populations that have different functions, like tumorigenesis, metastasis, relapse, and drug resistance [1]
We found that calmodulin-dependent protein kinase IIγ (CaMKIIγ) was highly activated and expressed in highly tumorigenic and stem-like cells enriched from culture conditioned for lung cancer oncospheres
We used real-time PCR to determine the mRNA expression for induced pluripotent stem cell factors, including OCT4, MYC, KLF4, and NANOG, which were associated with a stem-like phenotype
Summary
Phenotypic heterogeneity of cancer cells as a consequence of genetic change and environmental differences leads to formation of a tumor ecosystem composed of various cell populations that have different functions, like tumorigenesis, metastasis, relapse, and drug resistance [1]. Highly tumorigenic stem-like cells, considered tumor-initiating cells (TICs) or cancer stem cells (CSCs), perform a vital role in tumor initiation and development [2]. Such a population is responsible for tumor relapse after treatment. Due to the success of therapy targeted to driver genes, many patients with lung cancer have a good initial response to therapy; most experience a relapse within one year [4, 5]. Targeting the highly tumorigenic stemlike cell population has recently been suggested as a new approach to treat lung cancer
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