Deciphering the molecular mechanisms underlying the pathobiology of esophageal squamous cell carcinoma

  • Author / Creator
    Zhang, Hai-feng
  • Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers worldwide, largely due to a high frequency of tumor invasion/metastasis, chemoresistance and recurrence. In this study, we explored from different perspectives the molecular mechanisms behind these aggressive features of ESCC. 1) microRNAs are small non-coding RNAs that suppress gene expression at the post-transcriptional level, the deregulation of which have been shown to promote invasion/metastasis. We found that the miR-200b/200a/429 cluster was frequently downregulated in ESCC, which significantly correlated with unfavorable prognosis in ESCC patients. miR-200b suppressed the invasiveness of ESCC both in vitro and in vivo. Quantitative mass spectrometry identified 57 putative miR-200b targets, including Kindlin-2, which was found to mediate the role of miR-200b in the regulation of ESCC invasiveness by modulating the cytoskeletal and the adhesive machinery. 2) STAT3 has been widely recognized as an oncogene, whereas accumulating evidence from both experimental and clinical studies has suggested that STAT3 may also carry a tumor suppressor role. We hypothesized that the interplay between the two STAT3 isoforms, STAT3α and STAT3β, may be the key determinant of the opposing roles of STAT3 in cancer biology. We revealed that while STAT3β substantially increased the tyrosine705-phosphorylation, nuclear translocation and promoter occupancy/DNA-binding of STAT3α, it significantly decreased the transcription activity of STAT3 and its tumorigenic potential in ESCC cells. STAT3β also decreased the cancer stem cell population, and markedly sensitized ESCC cells to 5-flurouracil (5-FU) and cisplatin both in vitro and in iii vivo. We found that the STAT3β-induced increase in phospho-STAT3αY705 (pSTAT3αY705) is attributed to the decreased binding and dephosphorylation of STAT3α by PTP-MEG2, a protein tyrosine phosphatase. We found a significant correlation between the expression of STAT3β and pSTAT3αY705 and a longer survival in ESCC patients. Importantly, the prognostic value of pSTAT3αY705 was dependent on the expression status of STAT3β. 3) The presence of cancer stem cells within a tumor has been linked to chemoresistance and cancer recurrence. Using a lentiviral reporter expressing GFP and luciferase under the control of SRR2 (Sox2 regulatory region 2), two subpopulations of cells (i.e. GFP- and GFP+) were identified in ESCC based on the reporter responsiveness. Compared with RU (reporter-unresponsive) cells, RR (reporter-responsive) cells displayed a higher capacity in forming tumorspheres, contained a higher proportion of stem cell-like CD44High cells and were more chemoresistant to cisplatin. Importantly, we revealed that ROS (reactive oxygen species) induced by H2O2 was able to convert the less stem-like RU cells to the more stem-like RR cells. We found that the PI3K/AKT pathway activates MYC to promote the stemness in RR cells, which also mediates the ROS-induced RU-to-RR conversion. To conclude, this study has provided insights into the molecular mechanism underlying the pathobiology of ESCC, which may provide valuable prognostic and therapeutic targets in ESCC.

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    Doctor of Philosophy
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