title: The PI3K/AKT/c-MYC Axis Promotes the Acquisition of Cancer Stem-Like Features in Esophageal Squamous Cell Carcinoma.
abstract: The importance of intratumoral heterogeneity has been highlighted by the identification and characterization of cancer stem cells (CSCs). Based on the differential responsiveness to a Sox2 reporter, SRR2, we had found a novel dichotomy in esophageal squamous cell carcinoma (ESCC) cells, with reporter-responsive (RR) cells showing more CSC-like features than reporter-unresponsive (RU) cells. Specifically, RR cells exhibited significantly higher tumorsphere formation capacity, proportions of CD44(High) cells, chemoresistance to cisplatin, and tumorigenic potential in vivo. H2 O2 , a potent inducer of oxidative stress and reactive oxygen species, was found to induce a conversion from RU to RR cells; importantly, converted RR cells acquired CSC-like features. The PI3K/AKT/c-MYC signalling axis is important in this context, since pharmacologic blockade of PI3K-AKT or siRNA knockdown of c-MYC effectively inhibited the RR phenotype and its associated CSC-like features, as well as the H2 O2 -induced RU/RR conversion. In a cohort of 188 ESCC patient samples, we found a significant correlation between strong c-MYC expression and a short overall survival (p = .009). In conclusion, we have described a novel intratumoral heterogeneity in ESCC. The identification of the PI3K/AKT/c-MYC axis as a driver of CSC-like features carries therapeutic implications. Stem Cells 2016;34:2040-2051.
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China.|Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Chengsheng
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Abdulraheem
authors.initials: A
authors.lastname: Alshareef
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Gupta
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China.|Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China.|Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Xiu-E
authors.initials: XE
authors.lastname: Xu
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Ji-Wei
authors.initials: JW
authors.lastname: Jiao
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: En-Min
authors.initials: EM
authors.lastname: Li
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China.|Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Xu
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D055748:SOXB1 Transcription Factors; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Cancer stemness; Esophageal squamous cell carcinoma; Intra-tumoral heterogeneity; Oxidative stress; c-MYC