Abstract
BackgroundEsophageal cancer is the sixth-leading cause of cancer-related deaths worldwide. Cancer stem cells (CSCs) are the main reason for tumor relapse in esophageal squamous cell carcinoma (ESCC). The NOTCH pathway is important in preservation of CSCs, therefore it is possible to target such cells by targeting MAML1 as the main component of the NOTCH transcription machinery.MethodsIn present study we isolated the CD44+ ESCC CSCs and designed a MAML1-targeted therapy to inhibit the NOTCH signaling pathway. CSCs were isolated using magnetic cell sorting utilizing the CD44 cell surface marker. Several stem cell markers were analyzed in the levels of protein and mRNA expression. The isolated CSCs were characterized in vivo in NUDE mice. Biological role of MAML1 was assessed in isolated CD44+ CSCs. A drug resistance assay was also performed to assess the role of MAML1 in CD44+ CSCs with 5FU resistance.ResultsThe CD44+ CSCs had ability to form tumors in NUDE mice. MAML1 silencing caused a significant decrease (p = 0.019) and ectopic expression caused a significant increase in migration of CD44+ CSCs (p = 0.012). Moreover, MAML1 silencing and ectopic expression significantly increased and decreased 5FU resistance, respectively (p < 0.05). MAML1 silencing significantly increased the number of cells in G1 phase (p = 0.008), and its ectopic expression significantly increased the number of CD44+ CSCS in S phase (p = 0.037).ConclusionsMAML1 may be utilized for targeted therapy with a low side effect to eliminate the CD44+ CSCs through inhibition of canonical NOTCH pathway in ESCC patients.
Highlights
Esophageal cancer is the sixth-leading cause of cancer-related deaths worldwide
Cancer stem cells were isolated and characterized from an esophageal squamous cell carcinoma (ESCC) patient and the role of MAML1 as the main component of the NOTCH pathway was assessed in the biology of isolated ESCC-CSCs for the first time
Cell culture and sphere formation Fresh tissue was obtained from an 84-year old male ESCC patient who was undergone an esophagectomy before chemo-radio therapy
Summary
Cancer stem cells (CSCs) are the main reason for tumor relapse in esophageal squamous cell carcinoma (ESCC). The NOTCH pathway is important in preservation of CSCs, it is possible to target such cells by targeting MAML1 as the main component of the NOTCH transcription machinery. HES and HEY proteins are the main targets of the NOTCH pathway and act as transcriptional repressors through their basic helix-loophelix and WRPW domains to regulate several genes including cyclin D1 [25], NF-κB [26], p21 [17], MYC [27], and SLUG [28]. Cancer stem cells were isolated and characterized from an ESCC patient and the role of MAML1 as the main component of the NOTCH pathway was assessed in the biology of isolated ESCC-CSCs for the first time
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