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  • [Cancer Sci.] Hypoxia-inducible transgelin 2 selects epithelial-to-mesenchymal transition and γ-radiation-resistant subtypes by focal adhesion kinase-associated insulin-like growth factor 1 receptor activation in non-small-cell lung cancer cells.

    [Cancer Sci.] Hypoxia-inducible transgelin 2 selects epithelial-to-mesenchymal transition and γ-radiation-resistant subtypes by focal adhesion kinase-associated insulin-like growth factor 1 receptor activation in non-small-cell lung cancer cells.

    KAERI, 한국생명공학연구원 / 김인규*, 조은위*

  • 출처
    Cancer Sci.
  • 등재일
    2018 Sep 6. doi: 10.1111/cas.13791. [Epub ahead of
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    Abstract
    Microenvironment, such as hypoxia common to cancer, plays a critical role in the epithelial-to-mesenchymal transition (EMT) program, which is a major route of cancer metastasis and confers γ-radiation resistance to cells. Herein, we showed that transgelin 2 (TAGLN2), an actin-binding protein, is significantly induced in hypoxic lung cancer cells and that Snail1 is simultaneously increased, which induces EMT by downregulating E-cadherin expression. Forced TAGLN2 expression induced severe cell death; however, a small population of cells surviving after forced TAGLN2 overexpression showed γ-radiation resistance, which might promote tumor relapse and recurrence. These surviving cells showed high metastatic activity with an increase of EMT markers including Snail1. In these cells, TAGLN2 activated the insulin-like growth factor 1 receptor β (IGF1Rβ)/PI3K/AKT pathway by recruitment of focal adhesion kinase to the IGF1R signaling complex. Activation of the IGF1Rβ/PI3K/AKT pathway also induced inactivation of glycogen synthase kinase 3β (GSK3β), which is involved in Snail1 stabilization. Therefore, both the IGF1Rβ inhibitor (AG1024) and the PI3K inhibitor (LY294002) or AKT inactivation with MK2206 lower the cellular level of Snail1. Involvement of GSK3β was also confirmed by treatment with lithium chloride, the inducer of GSK3β phosphorylation, or MG132, the 26S proteasomal inhibitor, which also stabilized Snail1. In conclusion, the present study provides important evidence that hypoxia-inducible TAGLN2 is involved in the selection of cancer cells with enhanced EMT properties to overcome the detrimental environment of cancer cells.

     


    Author information

    Kim IG1,2, Lee JH1, Kim SY1, Hwang HM3, Kim TR1, Cho EW3.
    1
    Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon, Korea.
    2
    Department of Radiation Biotechnology and Applied Radioisotope, University of Science and Technology (UST), Daejeon, Korea.
    3
    Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.

     

    관련자료보기

    http://www.rmwebzine.re.kr/newshome/mtnmain.php?mtnkey=articleview&mkey=scatelist&mkey2=76&aid=2910

  • 키워드
    IGF1Rβ; Snail1; hypoxia; transgelin 2; γ-radiation resistance
  • 연구소개
    암에서 저산소증과 같은 미세 환경의 변화는 전이를 일으킬 수 있으며 또한 암세포의 γ-방사선 내성과 관계가 있는 상피-중간엽 전이(EMT) 프로그램에 결정적인 역할을 한다. 본 논문에서는 저산소환경의 폐암세포에서 액틴 결합 단백질로 알려진 transgelin2(TAGLN2)가 유의하게 유도되고, Snail1이 증가하여 E-cadherin 발현을 억제하여 EMT를 유도한다는 것을 보여주었다. in vitro에서 TAGLN2 과발현은 대부분의 세포사멸을 유도하였으나 일부 생존한 세포에서는 γ-방사선 저항성을 보였으며, 또한 종양의 재발과 전이를 촉진할 수 있음을 확인하였다. TAGLN2는 non-receptor tyrosine kinase인 FAK과 상호결합하여 receptor kinase인 IGF1Rβ을 활성화 시켰고 PI3K/AKT/GSK3β 경로를 활용 Snail1을 통해 E-cadherin을 조절함을 확인하였다. 이 연구는 hypoxia-inducible TAGLN2가 암세포의 유해한 환경을 극복하기 위해 향상된 EMT 특성을 가진 암세포의 생존과 선택에 관여한다는 것을 제안하였다.
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