Shp2 promotes liver cancer stem cell expansion by augmenting β-catenin signaling and predicts chemotherapeutic response of patients.

Src-homology 2 domain-containing phosphatase 2 (Shp2) has been reported to play an important role in the maintenance and self-renewal of embryonic and adult stem cells, but its role in cancer stem cells (CSCs) remains obscure. Herein, we observed high expression of Shp2 in both chemoresistant hepatocellular carcinomas (HCCs) and recurrent HCCs from patients. A remarkable increase of Shp2 was detected in sorted epithelial cell adhesion molecule-positive or cluster of differentiation 133-positive liver CSCs and in CSC-enriched hepatoma spheroids from patients. Up-regulated Shp2 facilitated liver CSC expansion by promoting the dedifferentiation of hepatoma cells and enhancing the self-renewal of liver CSCs. Mechanistically, Shp2 dephosphorylated cell division cycle 73 in the cytosol of hepatoma cells, and the dephosphorylated cell division cycle 73 bound β-catenin and facilitated the nuclear translocation of β-catenin, which promoted the dedifferentiation of hepatoma cells. Shp2 increased β-catenin accumulation by inhibiting glycogen synthase kinase 3β-mediated β-catenin degradation in liver CSCs, thereby enhancing the self-renewal of liver CSCs. Blockage of β-catenin abolished the discrepancy in liver CSC proportion and the self-renewal capacity between Shp2-depleted hepatoma cells and control cells, which further confirmed that β-catenin is required in Shp2-promoted liver CSC expansion. More importantly, HCC patients with low Shp2 levels benefited from transcatheter arterial chemoembolization or sorafenib treatment, but patients with high Shp2 expression did not, indicating the significance of Shp2 in personalized HCC therapy. Shp2 could promote HCC cell dedifferentiation and liver CSC expansion by amplifying β-catenin signaling and may be useful in predicting patient response to chemotherapeutics. (Hepatology 2017;65:1566-1580).

Xiang D ，Cheng Z ，Liu H ，Wang X ，Han T ，Sun W ，Li X ，Yang W ，Chen C ，Xia M ，Liu N ，Yin S ，Jin G ，Lee T ，Dong L ，Hu H ，Wang H ，Ding J ... -  《-》

Long non-coding RNA THOR promotes liver cancer stem cells expansion via β-catenin pathway.

Hepatocellular carcinoma (HCC) is a highly aggressive liver tumor containing cancer stem cells (CSCs), which participate in tumor invasion, therapeutic resistance, and tumor relapse leading to poor outcome and limited therapeutic options. Recently, a novel lncRNA, THOR (testis-associated highly conserved oncogenic long non-coding RNA), was characterized in human cancers and shown to exhibit an oncogenic role. However, the role of THOR in liver cancer stem cells (CSCs) remains obscure. Herein, we observed high expression of THOR in chemoresistant hepatocellular carcinomas (HCCs). A remarkable increase of THOR expression in OV6 or EpCAM-positive liver CSCs as well as in CSC-enriched hepatoma spheres. Interference THOR suppressed liver CSC expansion by inhibiting the dedifferentiation of hepatoma cells and decreasing the self-renewal ability of liver CSCs. Mechanistically, we found β-catenin as the downstream of THOR in HCC cells. The special β-catenin inhibitor FH535 abolished the discrepancy in liver CSC proportion and the self-renewal capacity between THOR knockdown HCC cells and control cells, which further confirmed that β-catenin was required in THOR promoted liver CSCs expansion. Moreover, interference THOR hepatoma cells were more sensitive to sorafenib treatment, indicates that HCC patients with low THOR expression may benefit from sorafenib treatment. Collectively, THOR was upregulated in liver CSCs and could promote HCC cells dedifferentiation and liver CSCs expansion by targeting β-catenin signaling.

Cheng Z ，Lei Z ，Yang P ，Si A ，Xiang D ，Zhou J ，Hüser N ... -  《-》

lncARSR promotes liver cancer stem cells expansion via STAT3 pathway.

Liver cancer stem cells (CSCs) have important functions in tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). lncARSR has been reported to play an important role in the maintenance and self-renewal of renal cancer stem cells, but its role in liver cancer stem cells (CSCs) remains obscure. Herein, we observed high expression of lncARSR in chemoresistant hepatocellular carcinomas (HCCs). A remarkable increase of lncARSR expression in EpCAM or CD133-positive liver CSCs as well as in CSC-enriched hepatoma spheres. Interference lncARSR suppressed liver CSC expansion by inhibiting the dedifferentiation of hepatoma cells and decreasing the self-renewal ability of liver CSCs. Mechanistically, we found STAT3 as the downstream of lncARSR in HCC cells. The special STAT3 inhibitor S3I-201 abolished the discrepancy in liver CSC proportion and the self-renewal capacity between lncARSR knockdown hepatoma cells and control cells, which further confirmed that STAT3 was required in lncARSR promoted liver CSCs expansion. More importantly, interference lncARSR HCC cells were more sensitive to sorafenib or cisplatin treatment. This maybe means that patients with low lncARSR levels benefited from cisplatin or sorafenib treatment, but patients with high lncARSR expression did not. Conclusion: lncARSR was upregulated in liver CSCs and could promote HCC cells dedifferentiation and liver CSCs expansion by targeting STAT3 signaling.

Yang C ，Cai WC ，Dong ZT ，Guo JW ，Zhao YJ ，Sui CJ ，Yang JM ... -  《-》

Prolonged inhibition of class I PI3K promotes liver cancer stem cell expansion by augmenting SGK3/GSK-3β/β-catenin signalling.

Liu F ，Wu X ，Jiang X ，Qian Y ，Gao J ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

miR-613 inhibits liver cancer stem cell expansion by regulating SOX9 pathway.

Liver cancer stem cells (CSCs) contribute to tumorigenesis, progression, drug resistance and recurrence of hepatocellular carcinoma (HCC). However, the underlying mechanism for the propagation of liver CSCs remains unclear. Herein, we observed miR-613 expression was downregulated in both chemoresistant and recurrent HCC patients. A remarkable decrease in miR-613 was detected in CD24 or OV6-positive liver CSCs and CSC-enriched hepatoma spheres. Down-regulation of miR-613 facilitated liver CSCs expansion by promoting the dedifferentiation of hepatoma cells and enhancing the self-renewal of liver CSCs. Mechanistically, bioinformatic and luciferase reporter analysis identified SOX9 as a direct target of miR-613. Overexpression of miR-613 inhibited the expression of SOX9 in HCC cells. Special SOX9 siRNA abolished the discrepancy in liver CSCs proportion and the self-renewal capacity between miR-613 overexpression hepatoma cells and control cells, which further confirmed that SOX9 was required in miR-613-inhibited liver CSCs expansion. Furthermore, hepatoma cells with miR-613 overexpression performed more sensitivity to cisplatin or sorafenib treatment. Conclusion: miR-613 could inhibit HCC cell dedifferentiation and liver CSCs expansion by targeting SOX9 signaling and may prove to be a novel therapeutic target for HCC patients.

Li B ，Liu D ，Yang P ，Li HY ，Wang D ... -  《-》