Relationship between cellular morphology and abnormality of SWI/SNF complex subunits in pancreatic undifferentiated carcinoma

• Published in: Journal of cancer research and clinical oncology Vol. 148; no. 11; pp. 2945 - 2957
• Main Authors: Yamamoto, Takeo, Kohashi, Kenichi, Yamada, Yutaka, Kawata, Jun, Sakihama, Kukiko, Matsuda, Ryota, Koga, Yutaka, Aishima, Shinichi, Nakamura, Masafumi, Oda, Yoshinao
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2022; Springer Nature B.V
• Subjects: Adenocarcinoma; Adenocarcinoma - pathology; Cadherins - genetics; Cancer; Cancer Research; DNA Helicases - genetics; DNA-Binding Proteins - genetics; E-cadherin; Formaldehyde; Gene expression; Genetic analysis; Hematology; Humans; Immunofluorescence; Immunohistochemistry; Internal Medicine; Medicine; Medicine & Public Health; Mesenchyme; mRNA; Nuclear Proteins - genetics; Oncology; Original Article – Clinical Oncology; Pancreas; Pancreatic carcinoma; Pancreatic Neoplasms; Paraffin; RNA, Messenger; SWI/SNF complex; Transcription Factors - genetics; Tumors; Vimentin; Western blotting; Pancreatic undifferentiated carcinoma; Epithelial-mesenchymal transition; ARID1A; SWI/SNF complex
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-021-03860-8

Purpose Pancreatic undifferentiated carcinoma (UDC) is a rare tumor with a worse prognosis than pancreatic ductal adenocarcinoma (PDAC). Recent study showed that UDC exhibits loss of SMARCB1, which is one of the subunits of the SWI/SNF complex. However, whether there are abnormalities of other SWI/SNF complex subunits in UDC has remained unknown. In this study, we attempted to clarify whether the loss of SWI/SNF complex subunits is related to the pathogenesis of UDC by comparing undifferentiated component (UC) and ductal adenocarcinoma component (DAC). Methods Genetic analysis of the ten UCs and six DACs was performed. The expression of ARID1A, SMARCA2, SMARCA4, SMARCB1, SMARCC1, and SMARCC2 in formalin-fixed, paraffin-embedded tumor tissues collected by surgical resection from 18 UDC patients was evaluated immunohistochemically. Moreover, two pancreatic cell lines were evaluated for the effects of siARID1A on the mRNA and protein expression of E-cadherin, vimentin, and epithelial-mesenchymal transition (EMT)-related markers by qRT-PCR, western blotting, and immunofluorescence staining. Results UCs tended to have a higher frequency of mutation in ARID1A, SMARCA4, and SMARCC2 than DACs. Immunohistochemically, UCs revealed reduced/lost expression of ARID1A (72%), SMARCB1 (44%), SMARCC1 (31%), and SMARCC2 (67%). Reduced/lost expression of ARID1A, SMARCB1, and SMARCC2 was significantly more frequently observed in UCs than in DACs. In the pancreatic cell lines, western blotting and qRT-PCR showed that the downregulation of ARID1A increased the expression of vimentin and EMT-related markers. Conclusion Our results suggest that the abnormality of SWI/SNF complex subunits, especially ARID1A, is one of the factors behind the morphological change of UDC.