iNOS promotes CD24(+)CD133(+) liver cancer stem cell phenotype through a TACE/ADAM17-dependent Notch signaling pathway.

The inducible nitric oxide synthase (iNOS) is associated with more aggressive solid tumors, including hepatocellular carcinoma (HCC). Notch signaling in cancer stem cells promotes cancer progression and requires Notch cleavage by ADAM (a disintegrin and metalloprotease) proteases. We hypothesized that iNOS/NO promotes Notch1 activation through TACE/ADAM17 activation in liver cancer stem cells (LCSCs), leading to a more aggressive cancer phenotype. Expression of the stem cell markers CD24 and CD133 in the tumors of patients with HCC was associated with greater iNOS expression and worse outcomes. The expression of iNOS in CD24+CD133+ LCSCs, but not CD24-CD133- LCSCs, promoted Notch1 signaling and stemness characteristics in vitro and in vivo, as well as accelerating HCC initiation and tumor formation in the mouse xenograft tumor model. iNOS/NO led to Notch1 signaling through a pathway involving the soluble guanylyl cyclase/cGMP/PKG-dependent activation of TACE/ADAM17 and up-regulation of iRhom2 in LCSCs. In patients with HCC, higher TACE/ADAM17 expression and Notch1 activation correlated with poor prognosis. These findings link iNOS to Notch1 signaling in CD24+CD133+ LCSCs through the activation of TACE/ADAM17 and identify a mechanism for how iNOS contributes to progression of CD24+CD133+ HCC.

Wang R ，Li Y ，Tsung A ，Huang H ，Du Q ，Yang M ，Deng M ，Xiong S ，Wang X ，Zhang L ，Geller DA ，Cheng B ，Billiar TR ... -  《-》

Notch signaling plays a crucial role in cancer stem-like cells maintaining stemness and mediating chemotaxis in renal cell carcinoma.

Xiao W ，Gao Z ，Duan Y ，Yuan W ，Ke Y ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

Notch and Wnt/β-catenin signaling pathway play important roles in activating liver cancer stem cells.

Wang R ，Sun Q ，Wang P ，Liu M ，Xiong S ，Luo J ，Huang H ，Du Q ，Geller DA ，Cheng B ... -  《Oncotarget》

Role of ADAM17 in invasion and migration of CD133-expressing liver cancer stem cells after irradiation.

Hong SW ，Hur W ，Choi JE ，Kim JH ，Hwang D ，Yoon SK ... -  《Oncotarget》

Musashi2 contributes to the maintenance of CD44v6+ liver cancer stem cells via notch1 signaling pathway.

Wang X ，Wang R ，Bai S ，Xiong S ，Li Y ，Liu M ，Zhao Z ，Wang Y ，Zhao Y ，Chen W ，Billiar TR ，Cheng B ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》