title: Differential role of Wnt signaling and base excision repair pathways in gastric adenocarcinoma aggressiveness.
abstract: Aberrant activation of Wnt and base excision repair (BER) signaling pathways are implicated in tumor progression and chemotherapy resistance in gastric adenocarcinoma. This study was conducted to clarify the role of E2F6 and RhoA, components of the Wnt signaling pathway, and SMUG1, a component of the BER pathway in gastric adenocarcinoma. Expression levels and clinicopathological significance of three biomarkers, namely E2F6, RhoA, and SMUG1, as potential signaling molecules involved in tumorigenesis and aggressive behavior, were examined using tissue microarray. Our analysis showed a relative increase in the expression of E2F6 in gastric adenocarcinoma with no lymph node metastasis (χ2, P = 0.04 and OR, P = 0.08), while overexpression of RhoA and SMUG1 was found more often in the diffuse subtype of gastric adenocarcinoma as compared to the intestinal subtype (χ2, P = 0.05, OR, P = 0.08 and χ2, P = 0.001, OR, P = 0.009, respectively). Higher expression of RhoA was frequently seen in tumors with vascular invasion (χ2, P = 0.01 and OR, P = 0.01). In addition, increased expression of SMUG1 was found more often in poorly differentiated tumors (χ2, P = 0.01 and OR, P = 0.01). The distinct phenotype of E2F6Low/SMUG1Highwas more common in poorly differentiated tumors (P = 0.04) and with omental involvement (P = 0.01). The RhoAHigh/SMUG1Highexpression pattern was significantly more often found in diffuse subtype compared to the intestinal subtype (P = 0.001) as well as in poorly differentiated tumors (P = 0.004). The E2F6Low/SMUG1Highand RhoAHigh/SMUG1Highphenotypes can be considered as aggressive phenotypes of gastric adenocarcinoma. Our findings also demonstrated the synergistic effect of RhoA and SMUG1 in conferring tumor aggressiveness in diffuse subtype of gastric adenocarcinoma.
authors.affiliation: Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Alireza
authors.initials: A
authors.lastname: Korourian
authors.affiliation: Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran.
authors.forename: Raheleh
authors.initials: R
authors.lastname: Roudi
authors.affiliation: Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran.|Department of Nuclear Medicine and Molecular Imaging, State University of New York at Buffalo, Buffalo, NY, 14214, USA.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Shariftabrizi
authors.affiliation: Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran.
authors.forename: Elham
authors.initials: E
authors.lastname: Kalantari
authors.affiliation: Danesh Pathobiology Lab, Tehran, Iran.
authors.forename: Kambiz
authors.initials: K
authors.lastname: Sotoodeh
authors.affiliation: Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran. Zahra.madjd@yahoo.com.|Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran. Zahra.madjd@yahoo.com.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Madjd
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004260:DNA Repair; D050701:E2F6 Transcription Factor / Q000032:analysis*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000473:pathology*; D046888:Tissue Array Analysis; D051981:Uracil-DNA Glycosidase / Q000032:analysis*; D060449:Wnt Signaling Pathway; D020742:rhoA GTP-Binding Protein / Q000032:analysis*
chemical_list: D050701:E2F6 Transcription Factor; C491744:E2F6 protein, human; C066737:RHOA protein, human; C498095:SMUG1 protein, human; D051981:Uracil-DNA Glycosidase; D020742:rhoA GTP-Binding Protein
keywords: Base excision repair; E2F6; Gastric cancer; RhoA; SMUG1; Wnt signaling pathway