ABSTRACT
Cancer stem cells (CSCs) are responsible for cancer formation, recurrence and drug resistance. c-Myc, one of the core markers for stem cells, has recently been considered to serve as a link between malignancy and 'stemness'. However, the precise function of c-Myc in colon CSCs is still unclear. In the present study, a subpopulation of colon CSCs expressing a CD133 surface phenotype was isolated from the human HT-29 cell line, which possess greater tumor sphere-forming efficiency and have higher expression of 'stemness'-associated genes compared with CD133-negative cells. Furthermore, it was demonstrated that c-Myc was highly expressed in CD133+ colon CSCs. Knockdown of c-Myc expression with small interfering RNA in colon CSCs can significantly inhibit tumor sphere formation, reduce the invasive and migratory capacity of CD133+ cells in vitro, and suppress the tumorigenicity of colon CSCs in vivo. In addition, it was suggested that c-Myc silencing may sensitize colon CSCs to chemotherapy-induced cytotoxicity via the downregulation of ABCG2 and ABCB5. These findings support a central role for c-Myc in maintaining the self-renewing and chemoresistant properties of colon CSCs.
ABSTRACT
BACKGROUND: As patients aged 75 years and older are often underrepresented in randomized clinical trials, the external validity of clinical trials-based recommendations in older gastric patients was still controversial. The aim of this study is to explore the recommended treatment strategy for locally advanced gastric cancer in elderly patients. METHODS: We designed our study to specifically evaluate the cancer-specific survival (CSS) of four subgroups of patients according to four different treatment modalities: adjuvant radiation (RT), surgery only, RT only and no surgery/no RT by analyzing the Surveillance, Epidemiology, and End Results (SEER)-registered database. Kaplan-Meier methods were adopted and multivariable Cox regression models were built for the analysis of survival outcomes and risk factors. RESULTS: The 5-year CSS was 43.8 % in adjuvant RT, 28.5 % in surgery only, 14.9 % in RT only and 1.4 % in no surgery/no RT, which had significant difference in univariate log-rank test (P < 0.001) and multivariate Cox regression (P < 0.001). Moreover, we observed significant survival benefits in adjuvant RT group in all age categories, including age 75-79 years, age 80-84 years and age ≥85 years (all P < 0.001). CONCLUSIONS: Surgery and adjuvant RT may be the recommended treatment strategy in elderly patients with locally advanced gastric cancer, especially for patients medically fit for the combined modality therapy.
Subject(s)
Adenocarcinoma/therapy , Stomach Neoplasms/therapy , Adenocarcinoma/mortality , Aged , Aged, 80 and over , Female , Humans , Kaplan-Meier Estimate , Male , Multivariate Analysis , Practice Guidelines as Topic , Proportional Hazards Models , SEER Program , Stomach Neoplasms/mortality , Treatment OutcomeABSTRACT
The present study was aimed to explore the role of c-Myc gene regulation in maintaining the self-renewal and drug-resistant properties of colon cancer stem cells (CSCs) and the underlying mechanism. CD133(+) cells were isolated by flow cytometry cell sorting from human HT29 cancer cells. A small interfering RNA (siRNA) against c-Myc was used, and the mRNA and protein expressions of c-Myc were investigated by real-time PCR and Western blotting, respectively. To evaluate the effect of c-Myc on the drug resistance of colon CSCs, CD133(+) cells transfected with c-Myc-siRNA were exposed to 5-FU, oxaliplatin, or their combination. The expressions of ATP-binding cassette (ABC) transporters, including ABCG2, ABCB5 and MDR-1, were detected by Western blotting. The results showed that c-Myc was highly expressed in CD133(+) colon CSCs, and the protein and mRNA expressions of c-Myc were effectively blocked by c-Myc siRNA. Furthermore, CD133(+) cells showed significantly increased survival rate in chemotherapy treatment, compared with CD133(-) cells. c-Myc silencing sensitized CD133(+) cells to chemotherapy-induced cytotoxicity and down-regulated the protein expression levels of ABCG2, MDR-1 and ABCB5. These results suggest c-Myc silencing may regulate the expressions of ABC transporters in colon CSCs, and enhance the sensitivity of CSCs to the chemotherapy.
