Abstract
Gastric cancer stem-like cells (GCSCs) have been identified to possess the ability of self-renewal and tumor initiation. However, the mechanisms involved remain largely unknown. Here, we isolated and characterized the GCSCs by side population (SP) sorting procedure and cultured sphere cells (SC) from human gastric cancer cell lines SGC-7901, BGC-823, MGC-803, HGC-27 and MKN-28. The sorting and culture assay revealed that SP cells proliferated in an asymmetric division manner. In addition, SP cells exhibited a higher potential of spheroid colony formation and greater drug resistance than non-SP cells (NSP). Moreover, the SC were found with enhanced capabilities of drug resistance in vitro and tumorigenicity in vivo. Sox2 mRNA and protein was highly and significantly overexpressed in the SP cells and SC. Importantly, downregulation of Sox2 with siRNA obviously reduced spheroid colony formation and doxorubicin efflux, as well as increased apoptosis rate in sphere cells in vitro and suppressed tumorigenicity in vivo. These results suggest that both SP cells and cultured SC enrich with GCSCs and that Sox2 plays a pivotal role in sustaining stem cell properties and might be a potential target for gastric cancer therapy.
Highlights
Gastric cancer (GC) is the second leading cause of cancer-related death worldwide[1]
We demonstrated that side population (SP) cells isolated from CD44 high expression GC cell lines and cultured sphere cells (SC) displayed stem cell characteristics, correlated to elevated levels of ATP-binding cassette transporters (ABC transporters) and transcription factor Sox2
The SP cells completely disappeared from GC cells when treated with verapamil, an ABC-transporter inhibitor
Summary
Gastric cancer (GC) is the second leading cause of cancer-related death worldwide[1]. Despite the development of surgery and chemotherapy, the 5-year survival rate across all stages is only about 20% due to metastasis, recurrence and multiple drug resistance (MDR). Recent studies have revealed the critical role of cancer stem-like cells (CSCs) or tumor initiating cells in tumorigenicity and metastasis. CSCs are defined as a small side population (SP) of cancer cells, with the capability of both self-renewal and pluripotency[2], mediating tumor initiation, metastasis, recurrence and drug resistance[3,4]. The possible existence of CSCs has been identified in leukemia[5,6], breast cancers[7,8] and other solid malignancies[6,9,10,11]. SP cells can be isolated by fluorescence activated cell sorter (FACS) that select cells exhibiting low fluorescence
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