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.
Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.
Min
M
Xu
Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
Aihua
A
Gong
Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.
Hongqiong
H
Yang
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Suraj K
SK
George
Department of Laboratory Medicine & Zhenjiang Key Laboratory of Medical Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.
Zhijun
Z
Jiao
Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.
Hongmei
H
Huang
Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.
Xiaomeng
X
Jiang
Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China. Electronic address: zjyouli1957@163.com.
Youli
Y
Zhang
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000813:Anilides; D000903:Antibiotics, Antineoplastic; C497483:CD44 protein, human; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C538724:HhAntag691; D018960:Hyaluronan Receptors; D009363:Neoplasm Proteins; D011725:Pyridines; C509239:SHH protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D004317:Doxorubicin
ABCG2; Chemoresistance; Gastric cancer xenograft; SHH-GLI