《Table 1 Effects of CITED2 in different cancer》

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《CITED2 and the modulation of the hypoxic response in cancer》

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The previous studies support the notion that CITED2 has context-dependent roles in cancer（Table 1）.Although less extensively，CITED2 has also been shown to play a role in some other cancers，such as undifferentiated pleomorphic sarcoma，osteosarcoma，thyroid，and ovarian cancers[111-114].CITED2 is also likely to play a role in an important aspect of tumor development related to cancer stem cells（CSCs）.It is currently accepted that tumors originate from CSCs，which may derive from normal stem or progenitor cells that have lost the ability to self-regulate proliferation and quiescence[115，116].Interestingly，an abnormal expression of core pluripotency transcription factors，such as OCT4，SOX2，NANOG，TBX3 and KLF4，has also been associated with CSCs，suggesting that the expression of pluripotent gene regulatory network factors may contribute to the conversion of normal cells into CSCs[117].In murine embryonic stem cells，Cited2 controls the expression of Nanog，Tbx3，Klf4 and Oct4[118，119]，and in adult stem cells it was associated with self-renewal，survival and quiescence[52，120，121].Moreover，the CITED2-target gene BMI1，was shown to be involved in various CSC functions[122-124].Thus，in particular circumstances，an anomalous increase of CITED2 expression may contribute to uncontrolled self-renewal and proliferation of stem cells and originate CSCs.Supporting this notion，a subset of patients with AML present an aberrantly elevated expression of CITED2 in CD34-positive leukemic cells compared to normal cells[101].The imbalanced CITED2expression due to a failure of PU.1 repression during normal myelopoiesis is likely to promote the initiation and maintenance of leukemia，and potentiate the establishment of a subset of multipotent leukemic stem cells[101].On the other hand，patients with NSCLC expressing CITED2/MYC/E2F3/p21CIP have a poor prognosis[110]，but CITED2was demonstrated to repress the expression of CSCs markers in NSCLC-stem cells and enhance their sensitivity to ionizing radiations in combination with butyrate treatment[125].Therefore，the potential role played by CITED2 in the generation and maintenance of CSCs may vary with the nature of the tumor.Interestingly，increasing evidence indicates that HIFs regulate the sub-populations of CSCs in BC，CRC，and AML，for instance[126].Therefore，studies to determine whether abnormal levels of CITED2 are important in CSC functions and weather CITED2-mediated inhibition of HIF signaling is on the basis of these functions should be pursued.