Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation (Cell Death and Differentiation, 2014, 21(4):568-81)

報告日期: 2015/03/27
報告時間: 17:10/18:00
報告學生: 杜洪齊
講評老師: 邱文泰
附件下載: 下載[1479-1425858733-1.pdf] 

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

Cell Death and Differentiation 2014;21(4):568-81

Dai W, Bai Y, Hebda L, Zhong X, Liu J, Kao J, Duan C

Student: Hung-Chi Tu                                   Time:2015/3/27 17:10-18:00

Commentator: Dr. Wen-Tai Chiu                   Place: Room 602


Colorectal cancer is a leading cause of cancer-related deaths. Previous studies have reported that Ca2+ deficiency is a risk factor to abnormal colonic epithelial growth. However, the mechanism underlying Ca2+ deficiency-induced epithelial growth remains unclear. To unravel this, the zebrafish yolk sac skin was used as an in vivo epithelial model. NaR cells are Ca2+-transporting epithelial cells specifically located on zebrafish yolk sac skin and responsible for Ca2+ uptake from surrounding water. Trpv5/6, the zebrafish ortholog of human transient receptor potential channels TRPV5 and TRPV6, is a Ca2+-selective channel specifically expressed in NaR cells. Under low [Ca2+] environment, the proliferation of trpv5/6-expressing NaR cells were significantly increased on yolk sac skin. Double-label in situ hybridization analysis showed that igfbp5a, a gene encoding a high-affinity IGF-binding protein 5a, was co-localized with trpv5/6-expressing NaR cells. IGF transduced through the IGFR-PI3K-Akt is known as one of the regulatory mechanisms of cell proliferation. The results of immunostaining and in situ hybridization showed that the pAkt level and the proliferation of NaR cells were increased under low [Ca2+] environment. Inhibition of Igfbp5a, IGF1R, PI3K, Akt and Trpv5/6 attenuates low [Ca2+]-induced Akt activation and NaR cell proliferation. Artificially evoked membrane depolarization could mimic the low [Ca2+]-induced Akt activation and NaR cell proliferation under normal [Ca2+] environment, and reverse the attenuation effect of Trpv5/6 inhibitor on Akt activation under low [Ca2+] environment. The similar PI3K-PDK1-Akt activation through TRPV6 under low [Ca2+] environment was also shown in human colon cancer cell line. These findings suggested that low [Ca2+] might induce membrane depolarization through TRP channel, leading to the activation of IGF signaling, and finally contributing to abnormal epithelial cell proliferation.


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