Sonic hedgehog-glioma associated oncogene homolog 1 signaling enhances drug resistance in CD44(+)/Musashi-1(+) gastric cancer stem cells.

Drug resistance in gastric cancer largely results from the gastric cancer stem cells (GCSCs), which could be targeted to improve the efficacy of chemotherapy. In this study, we identified a subpopulation of GCSCs enriched in holoclones that expressed CD44(+)/Musashi-1(+) stem cell biomarkers, capable of self-renewal and proliferation. Enriched CD44(+)/Musashi-1(+) GCSCs demonstrated elevated expression of sonic hedgehog (SHH) and glioma-associated oncogene homolog 1 (GLI1), the well-known signaling pathway molecules involved in the drug resistance. Further, CD44(+)/Musashi-1(+) cells exhibited high drug efflux bump activity and were resistant to doxorubicin (Dox)-induced apoptosis, and unregulated the ATP-binding cassette sub-family G member 2 (ABCG2) expression,. The above effects on apoptosis were reversed in the presence of GLI inhibitors, GANT61 and GDC-0449, or by the knockdown of GLI1/SHH. Upon knockdown of GLI1, expression of ABCG2 was downregulated the antitumor effects were significantly improved as observed in the gastric cancer xenograft. Collectively, our study revealed that co-expression of CD44(+)/Musashi-1(+) could be used to identify GCSCs, which also accounts for the drug resistance in gastric cancer. SHH-GLI and its downstream effector ABCG2 could be better targeted to possibly improve the efficacy of chemotherapy in drug-resistant gastric cancers.

Xu M ，Gong A ，Yang H ，George SK ，Jiao Z ，Huang H ，Jiang X ，Zhang Y ... -  《-》

GLI1-mediated regulation of side population is responsible for drug resistance in gastric cancer.

Yu B ，Gu D ，Zhang X ，Li J ，Liu B ，Xie J ... -  《Oncotarget》

Genistein attenuates cancer stem cell characteristics in gastric cancer through the downregulation of Gli1.

Yu D ，Shin HS ，Lee YS ，Lee D ，Kim S ，Lee YC ... -  《-》

RETRACTED: CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance.

Gastric cancers may harbor a subset of cells with cancer stem cell (CSC) properties, including chemotherapy resistance, and CD44 is a gastric CSC marker. The Hedgehog (HH) pathway is a key developmental pathway that can be subverted by CSCs during tumorigenesis. Here, we examine the role of HH signaling in CD44(+) gastric cancer cells. Gastric cancer cell lines, tumor xenografts, and patient tumors were examined. Gastric cancer cell lines AGS, MKN-45, and NCI-N87 grown as spheroids or sorted for CD44(+) were found to have upregulation of HH pathway proteins. HH inhibition using Smoothened (Smo) shRNA or vismodegib (VIS) decreased spheroid formation and colony formation. CD44(+) cells, compared with unselected cells, were also resistant to 5-fluorouracil and cisplatin chemotherapy, and this resistance was reversed in vitro and in xenografts with Smo shRNA or VIS. CD44(+) cells also had significantly more migration, invasion, and anchorage-independent growth, and these properties could all be blocked with HH inhibition. Clinical tumor samples from a phase II trial of chemotherapy with or without VIS for advanced gastric cancer were analyzed for CD44 expression. In the chemotherapy alone group, high CD44 expression was associated with decreased survival, whereas in the chemotherapy plus VIS group, high CD44 expression was associated with improved survival. HH signaling maintains CSC phenotypes and malignant transformation phenotypes in CD44(+) gastric cancer cells, and HH inhibition can reverse chemotherapy resistance in CD44(+) cells. Gastric cancer is a heterogeneous disease, and the strategy of combining chemotherapy with HH inhibition may only be effective in tumors with high CD44 levels.

Yoon C ，Park DJ ，Schmidt B ，Thomas NJ ，Lee HJ ，Kim TS ，Janjigian YY ，Cohen DJ ，Yoon SS ... -  《-》

miR-98-5p inhibits gastric cancer cell stemness and chemoresistance by targeting branched-chain aminotransferases 1.

Gastric cancer stem cells (GCSCs) have been used as a therapeutic target. This study aims to estimate the role of miR-98-5p (termed miR-98) in the development of GCSCs. The expression of miR-98 in CD44+ GCSCs was verified by RT-PCR. The miR-98 was overexpressed in CD44+ GCSCs by Lentivirus. The ability of self-renewal, invasion, chemoresistance and tumorigenicity was detected in vitro or in vivo after overexpression of miR-98. The target genes of miR-98 were predicted and verified by luciferase reporter assays. The effects miR-98/BCAT1 signaling on the chemoresistance and tumorigenicity of CD44+ GCSCs were investigated in a xenograft model by rescue experiments. We have shown that miR-98 was decreased in CD44+ GCSCs. The overexpression of miR-98 could inhibit the expression of stem-related genes and the ability of self-renewal, invasion, and tumorigenicity of GCSCs. Also, we found that miR-98 overexpression enhances the sensitivity to cisplatin treatment in vitro. Using a xenograft model, we showed that miR-98 overexpression reversed paclitaxel resistance to CD44+ GCSCs. Finally, we found that branched-chain aminotransferases 1 (BCAT1) is a target gene of miR-98. Overexpressed BCAT1 reversed xenograft tumor formation ability and attenuated the paclitaxel chemosensitivity induced by miR-98 downregulation. Furthermore, BCAT1 restoration affected the expression of invasion and drug resistance-related genes. This study revealed miR-98 inhibits gastric cancer cell stemness and chemoresistance by targeting BCAT1, suggesting that this miR-98/BCAT1 axis represents a potential therapeutic target in gastric cancer.

Zhan P ，Shu X ，Chen M ，Sun L ，Yu L ，Liu J ，Sun L ，Yang Z ，Ran Y ... -  《-》