ABCG2/V-ATPase was associated with the drug resistance and tumor metastasis of esophageal squamous cancer cells

Abstract

BackgroundATP-binding cassette sub-family G member 2 (ABCG2) is a protein that in humans is encoded by the ABCG2 gene. ABCG2 participates in efflux of many chemotherapeutic agents. ABCG2 is often expressed in hematopoietic progenitor or stem cells. Vacuolar-H + −ATPase (V-ATPase) plays a key role in adjusting and maintaining intracellular pH and in regulating the drug tolerance of cells. The TNM Classification of Malignant Tumours (TNM) is a cancer staging system that describes the extent of cancer in a patient’s body. In this study, the expression of ABCG2 and V-ATPase in esophageal squamous cancer cells was detected.MethodsImmunohistochemistry staining and Immunofluorescence double staining were used to detect the expression of ABCG2 and V-ATPase in in 66 cases of esophageal squamous cancer cells. Associations and differences in expression of ABCG2 with that of V-ATPase were analyzed.ResultsPositive staining patterns for both ABCG2 (66.67%) and V-ATPase (68.18%) were located mainly in the plasma membrane and cytoplasm. Marked differences in expression were also shown (P < 0.001) among 3 groups of pathological grades and TNM stages in these carcinomas. Marked differences were also found for ABCG2 expression between the two groups in the pathological grades and in the TNM staging groups (P < 0.01), but not between the αb and βgroups. V-ATPase expression was statistically significant between the 2 groups in the pathological grades and TNM stages (P < 0.05). This was not evident between α and β groups of pathological grades or between αb and βof the TNM stages. Marked differences in expression of ABCG2 and V-ATPase were found between metastatic and non-metastatic groups in the same carcinomas (P < 0.0001). There was also a clear correlation between the expression of ABCG2 and V-ATPase (P ≤ 0.001) in the various groups of pathological grades and TNM stages.ConclusionsBoth ABCG2 and V-ATPase were over-expressed in esophageal squamous cancer cells. Their expression was associated with pathological grade, TNM stage and tumor metastasis in esophageal squamous cancer cells, suggesting interaction relationship between them. ABCG2 and V-ATPase expression may be strongly associated with drug resistance and tumor metastasis.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3823783918433897

Reversing effect and mechanism of soluble resistance-related calcium-binding protein on multidrug resistance in human lung cancer A549/DDP cells

“…Huang et al demonstrated that ABCA5 was upregulated in the stem cell-like side population of lung cancer PLC/PRF/5 cells. Drug resistance is one major property of cancer stem cells (19)(20)(21). The present study demonstrated that the expression of ABCA2 and 5 was elevated in A549/DDP cells and mediated by Sorcin.…”

The Function of V-ATPases in Cancer

“…Lung and esophageal tumors expressing higher levels of V-ATPase were more likely to be drug resistant (71,107). Similarly, high expression in ovarian tumors was associated with worse survival outcomes (96).…”

“…Subsequent work demonstrated that the V-ATPase is present on the plasma membrane of invasive breast cancer cells, but not noninvasive breast cancer cells, and participates in control of cytoplasmic pH (175). The V-ATPase has since been found to be expressed on the plasma membranes of numerous invasive cancer cell types, including melanoma, Ewing sarcoma, and breast, liver, lung, ovarian, esophageal, prostate, and pancreatic cancers (9,21,23,24,63,71,90,107,125,136,176,216). Furthermore, overexpression of particular V-ATPase subunits has been observed in both human cancer cell lines and human tumor samples.…”

Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistance in cancer

“…In a separate study, expression of the V 1 C1 subunit, which bridges between the V 1 and V o domains, was detectable in all examined stages of Barrett's esophagus (a precursor lesion for ESCC associated with an ~0.3% annual risk of progression to adenocarcinoma) using immunohistochemistry (IHC), indicating that its increased expression may play a role early in the transformation in these tissues 28. Interestingly, immunofluorescence staining revealed that at least a proportion of V‐ATPase was localized to the plasma membrane in ESCC cells 29. Furthermore, a recent detailed study using IHC showed that the V 1 E1 subunit was overexpressed in esophageal squamous cell carcinoma (ESCC) compared to normal esophagus.…”

“…Increased cancer cell invasive activity is frequently associated with aberrant V‐ATPase plasma membrane localization suggesting that increased acidification of the extracellular space plays an important role 29, 33, 34, 37, 47, 48, 49, 50, 51, 52…”