SOX2/SALL4 stemness axis modulates Notch signaling genes to maintain self-renewal capacity of esophageal squamous cell c
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SOX2/SALL4 stemness axis modulates Notch signaling genes to maintain self‑renewal capacity of esophageal squamous cell carcinoma Mohammad Mahdi Forghanifard1 · Paniz Kasebi1 · Mohammad Reza Abbaszadegan2 Received: 16 July 2020 / Accepted: 15 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Stemness phenotype is considered as the centerpiece of cancer biology due to its potential in conventional chemo-radiotherapy resistance and tumor recurrence after clinical intervention. This feature in tumor mass belongs to activation of core regulatory stemness factors and different cell signaling pathways in cancer stem cells. We aimed in this study to elucidate contribution of Notch signaling pathway in stemness state of esophageal squamous cell carcinoma (ESCC) through their relevance with stem cell markers SOX2 and SALL4. 50 ESCC tumor and related margin normal tissues were considered and categorized based on SOX2/SALL4 expression pattern, and mRNA levels of Notch signaling genes including ligands, receptors, target genes, and transcriptional coactivator were analyzed in the selected groups using qRT-PCR. Concomitant overexpression of stem cell markers SOX2 and SALL4 in ESCCs upregulated the involved genes in Notch signaling pathway. Upregulation of Notch pathway genes associated with depth of tumor invasion and lymph node metastasis of ESCC. Based on biological function of SOX2 and SALL4 axis in stemness state potential, our results may suggest contribution of Notch signaling pathway in self-renewal capacity of ESCCs, as well as invasion and metastasis of the disease. To the best of our knowledge, this is the first report elucidating the crosstalk between SOX2/SALL4 stemness factors and Notch signaling pathway in cancer research. Keywords SOX2 · SALL4 · Notch signaling pathway · Stemness state · ESCC Abbreviations CSCs Cancer stem cells EMT Epithelial mesenchymal transition ESCs Embryonic stem cells ESCC Esophageal squamous cell carcinoma iPS Induced pluripotent stem TF Transcription factor
* Mohammad Mahdi Forghanifard [email protected]; [email protected] 1
Department of Biology, Damghan Branch, Islamic Azad University, Cheshmeh‑Ali Boulevard, Sa’dei Square, P.O. Box: 3671639998, Damghan, Islamic Republic of Iran
Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
2
Background Stemness state of tumor cells is an important property for the maintenance of survival and self-renewal, as well as progression and development of a variety of malignancies. This critical feature of cancer is established in tumor mass specifically by a subpopulation of tumor cells called cancer stem cells (CSCs), enhancing self-renewal capacity, progression, metastasis, and reproliferation of tumors. It has been suggested that the core regulatory transcription factors (TFs) of the stemness state in CSCs comprise OCT4, SOX2, KLF4, NANOG, and SALL4. Stemness is probably sustained in CSCs through a positive feedback loop in expression of
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