ABCG2 Expression Is an Independent Unfavorable Prognostic Factor in Esophageal Squamous Cell Carcinoma

Tsunoda, Shigeru; Okumura, Tomoyuki; Ito, Takahiro; Kondo, Kan; Ortiz, Cristián; Tanaka, Eiji; Watanabe, Go; Itami, Atsushi; Sakai, Yoshiharu; Shimada, Yutaka

doi:10.1159/000106787

Cited by 67 publications

(49 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A significant correlation was found between ABCG2 expression and clinical stage and lymph node metastasis. In accordance with research in acute myeloid leukemia (11,27,28), adult acute lymphoblastic leukemia (29), non-small cell lung cancer (15) and esophageal squamous cell carcinoma (14), positive expression of ABCG2 may accelerate progression and metastasis in HNSCC. However, no significant correlation, only an increasing trend between ABCG2 expression and histological grade, was observed in the tumor tissues of the laryngeal and nasopharyngeal cancers.…”

Section: Discussionsupporting

confidence: 67%

See 1 more Smart Citation

Expression and function of ABCG2 in head and neck squamous cell carcinoma and cell lines

Shen

Dong

et al. 2011

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Abstract. Overexpression of breast cancer resistance protein, the ATP-binding cassette, subfamily G, member2 (BCRP/ABCG2), confers multidrug resistance to tumor cells and often limits the efficacy of chemotherapy. The aim of this study was to investigate the expression and functional activity of ABCG2 in head and neck squamous cell carcinoma (HNSCC) and corresponding cell lines. Immunohistochemistry was performed to investigate the presence of the ABCG2 transporter in HNSCC tissues. Expression of ABCG2 in the Hep-2, Hep-2T, CNE and FaDu cell lines was analyzed by real-time quantitative reverse transcription-polymerase chain reaction and Western blotting at the levels of messenger RNA (mRNA) and protein, respectively. The drug sensitivity of the above four cell lines to mitoxantrone was detected using MTT, and the drug accumulation of mitoxantrone was analyzed by flow cytometry. Positive expression of ABCG2 was detected in 52.04% of the laryngeal cancer samples from 98 patients, in 65% of the 40 hypopharyngeal cancer samples and in 58.82% of the 34 nasopharyngeal cancer samples. The level of expression was found to be correlated with tumor TNM stage (P<0.05) and lymph node metastasis (P<0.01). All four HNSCC cell lines expressed ABCG2 at the mRNA and protein levels. The levels of ABCG2 expression in the four cell lines were significantly correlated with the function and sensitivity to mitoxantrone. The addition of fumitremorgin C at a concentration of 5 µM to mitoxantrone treatment caused a varied increase in mitoxantrone accumulation of 1.09-fold, 1.33-fold (P<0.01), 1.4-fold (P<0.01) and 1-fold in the Hep-2, Hep-2T, CNE and FaDu cells, respectively. Expression of ABCG2 varied among the different types of carcinoma tissues and each HNSCC cell line, and it induced multidrug resistance and separation of cancer stem cells attributing to its efflux pump function. Thus, ABCG2 expression may be an unfavorable prognostic factor for HNSCC. Due to the negligible expression and function of ABCG2, we suggest that the FaDu cell line is suitable to be a negative control in studies involving HNSCC. Taken together, ABCG2 is a promising universal biomarker of cancer stem cells and a target gene for HNSCC chemotherapy.

show abstract

Section: Discussionsupporting

confidence: 67%

“…ABCG2 overexpression has been observed in many cell lines and tumor types (7)(8)(9)(10)(11)(12)(13)(14)(15)(16), where it functions to pump a wide variety of endogenous and exogenous compounds out of cells (17)(18)(19)(20)(21). ABCG2 was demonstrated to be associated with cancer stem cells and multidrug resistance (22,23).…”

Section: Introductionmentioning

confidence: 99%

Expression and function of ABCG2 in head and neck squamous cell carcinoma and cell lines

Shen

Dong

et al. 2011

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

show abstract

“…11 These in vitro studies have correlates in the clinical setting, where the expression and activity of ABCG2 has been linked to radiotherapy resistance. 12 Interestingly, several studies suggest that ABCG2 may also be an indicator of poor prognosis in some tumors, including lung, 36 breast, 37 and esophageal cancers 38 even in the absence of drug treatment. Together, these observations suggest a role for ABCG2 in general tumor cell survival independent of its well-characterized drug efflux function.…”

Section: Discussionmentioning

confidence: 99%

A role for ABCG2 beyond drug transport: Regulation of autophagy

et al. 2016

View full text Add to dashboard Cite

The ABC drug transporters, including ABCG2, are well known for their ability to efflux a wide spectrum of chemotherapeutic agents, thereby conferring a multidrug-resistant phenotype. However, studies over the past several years suggest that the ABC transporters may play additional role(s) in cell survival in the face of stress inducers that are not ABCG2 substrates (i.e., nutrient deprivation, ionizing radiation, rapamycin). The mechanism by which this occurs is largely unknown. In the present study, using several cancer cell lines and their ABCG2-overexpressing sublines, we show that cells overexpressing ABCG2 were more resistant to these stressors. This resistance was associated with an elevated level of autophagy flux, as measured by a higher rate of SQSTM1/p62 degradation and greater accumulation of LC3-II when compared to parental cells. Knockdown of ABCG2 reduced autophagic activity in resistant cells to a level similar to that observed in parental cells, confirming that the enhanced autophagy was ABCG2-dependent. Moreover, using cell viability, apoptosis, and clonogenic assays, we demonstrated that the ABCG2-expressing cells were more resistant to amino acid starvation and radiation-induced cell death. Importantly, knockdown of the critical autophagy factors ATG5 and ATG7 greatly reduced cell survival, verifying that enhanced autophagy was critical for this effect. Taken together, these data indicate that autophagy induced by various stressors is enhanced/accelerated in the presence of ABCG2, resulting in delayed cell death and enhanced cell survival. This defines a new role for this transporter, one with potential clinical significance.

show abstract

“…CSCs display greater resistance to radioand chemotherapy compared with more differentiated tumor cells, which indicates that the CSC subset can escape from conventional cancer therapy to initiate and perpetuate tumorigenesis (35). In multiple independent studies, the CSC population has been associated with poor patient prognosis in ESCC, which is the sixth leading cause of cancer deaths worldwide (28,36,37). Huang and colleagues reported that the CSC population in ESCC displays robust resistance to radio-and chemotherapy (38) and correlates with the risk of mortality in this disease.…”

Section: Discussionmentioning

confidence: 99%