Expression of multidrug-resistance-related proteins P-glycoprotein, glutathione-S-transferases, topoisomerase-II and lung resistance protein in primary gastric cardiac adenocarcinoma.
OBJECTIVE
Multidrug resistance (MDR) is closely correlated to an unfavorable prognosis in various human cancers. However, the clinical significance of the expression of MDR-related proteins p-glycoprotein (PGP), glutathione-s-transferases (GST-pi), topoisomerase-II (Topo-II) and lung resistance protein (LRP) in primary gastric cardiac adenocarcinoma (PGCA) remains unclear. In this present study, the total of the four kinds of MDR-related proteins mentioned above were detected by using immunohistochemistry, and their clinical significance in chemoresistance were also investigated.


METHODS
This retrospective study included 69 resected specimens from patients with PGCA. The expression of PGP, GST-pi, Topo-II and LRP in formalin-fixed paraffin-embedded tissue sections was determined by a labelled streptavidin-biotin immunohistochemical technique, and the results were analyzed in correlation with clinicopathological data. None of these patients received chemotherapy prior to surgery.


RESULTS
The positive rates of expression of PGP, GST-pi, Topo-II and LRP in malignant tissues (49.2%, 75.4%, 68.1% and 58%, respectively) were all higher than that of the normal tissues(0, 30%, 20% and 0, respectively, P < 0.01). PGP expression in tumors that had metastasized was significantly more frequent than in tumors that had not metastasized (67.5% vs 24.1%, P < 0.01). The expression of PGP was closely related with clinicopathologic staging (staging 1/2 vs 3/4, 28.6% vs 58.3%, P < 0.05). No significant correlation was shown between PGP and increasing differentiated degree (40%, 42.4% and 61.5%, P > 0.05). GST-pi expression status progressively increased with increasing differentiated degree (40%, 75.8% and 88.5%, P < 0.05) and clinicopathologic stage (staging 1/2 vs 3/4, 57.1% vs 83.3%, P < 0.05). In addition, a significant positive correlation was also observed between GST-pi and lymphatic metastasis (with vs. without metastasis, 87.5% vs 58.6%, P < 0.05). The expression of Topo-II was associated with increasing differentiated degree (33.3%, 69.7 and 80.7%, P < 0.01). No significant differences with Topo-II expression were found in relation to the clinicopathologic stage (staging 1/2 vs 3/4, 57.1% vs 72.9%, P > 0.05) and lymphatic metastasis (with vs. without metastasis, 65.0% vs 72.4%, P > 0.05). Moreover, a significant difference with the expression of LRP was found in relation to the clinicopathologic stage (staging 1/2 vs 3/4, 38% vs 66.6%, P < 0.05), and lymphatic metastasis (with vs without metastasis, 70.0% vs 41.4%, P < 0.05). Comparing the well, moderately and poorly differentiated cohort, a non-statistical increasing trend towards LRP expression status was noted (50.0%, 54.5% and 65.3%, respectively, P > 0.05). Besides, the co-expression of all four tested MDR-related proteins also existed. The positive rates of co-expression of PGP and GST-pi, PGP and Topo-II, PGP and LRP, GST-pi and Topo-II, LRP and GST-pi, LRP and Topo-II, PGP, GST-pi, Topo-II and LRP in malignant cells were 23.2%, 15.9%, 11.6%, 13.0, 26.1, 7.24, 5.8, respectively.


CONCLUSIONS
MDR-related proteins PGP, GST-pi, Topo-II alpha and LRP are involved in multiple mechanisms of drug resistance in PGCA. Combined determination of PGP, GST-pi, Topo-II and LRP may be prospectively valuable for optimizing the chemotherapy regimes, developing high quality anti-cancer drugs, and further predicting the outcomes of those patients with PGCA.
Shi
Hongcan
H
Department of Cardiothoracic Surgery, Clinical College, Yangzhou University, Yangzhou, Jiangsu Province, China. shihongcan@gmail.com.cn
Lu
Dan
D
Shu
Yusheng
Y
Shi
Weiping
W
Lu
Shichun
S
Wang
Kang
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D000230:Adenocarcinoma / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D000328:Adult; D000368:Aged; D002299:Cardia / Q000737:chemistry* / Q000473:pathology; D004250:DNA Topoisomerases, Type II / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051549:Glutathione S-Transferase pi / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D009367:Neoplasm Staging; D015388:Organelles / Q000737:chemistry; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020394:Vault Ribonucleoprotein Particles / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000099187:Major Vault Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004250:DNA Topoisomerases, Type II; D051549:Glutathione S-Transferase pi; D009363:Neoplasm Proteins; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C496556:GSTP1 protein, human