Expression and localization of sterile alpha motif domain containing 5 is associated with cell type and malignancy of biliary tree

Abstract

Cholangiocarcinoma (CC) is a type of relatively rare neoplasm in adenocarcinoma. The characteristics of CCs as well as biliary epithelial cells are heterogeneous at the different portion of the biliary tree. There are two candidate stem/progenitor cells of the biliary tree, i.e., biliary tree stem/progenitor cell (BTSC) at the peribiliary gland (PBG) of large bile ducts and liver stem/progenitor cell (LPC) at the canals of Hering of peripheral small bile duct. Although previous reports suggest that intrahepatic CC (ICC) can arise from such stem/progenitor cells, the characteristic difference between BTSC and LPC in pathological process needs further investigation, and the etiology of CC remains poorly understood. Here we show that Sterile alpha motif domain containing 5 (SAMD5) is exclusively expressed in PBGs of large bile ducts in normal mice. Using a mouse model of cholestatic liver disease, we demonstrated that SAMD5 expression was upregulated in the large bile duct at the hepatic hilum, the extrahepatic bile duct and PBGs, but not in proliferating intrahepatic ductules, suggesting that SAMD5 is expressed in BTSC but not LPC. Intriguingly, human ICCs and extrahepatic CCs exhibited striking nuclear localization of SAMD5 while the normal hilar large bile duct displayed slight-to-moderate expression in cytoplasm. In vitro experiments using siRNA for SAMD5 revealed that SAMD5 expression was associated with the cell cycle regulation of CC cell lines. Conclusion: SAMD5 is a novel marker for PBG but not LPC in mice. In humans, the expression and location of SAMD5 could become a promising diagnostic marker for the cell type as well as malignancy of bile ducts and CCs.

Sex specific associations in genome wide association analysis of renal cell carcinoma

“…Also, a significant over expression of SAMD5 in tumours from current and TCGA datasets suggests its potential role in RCC pathogenesis. Although not previously implicated in RCC, SAMD5 overexpression has been found to be associated with bile duct and cholangiocarcinoma 35 . BTBD11 gene codes for an ankyrin repeat and BTB/POZ domain-containing protein involved in regulation of proteolysis and protein ubiquitination.…”

Multiomic Profiling Identifies cis-Regulatory Networks Underlying Human Pancreatic β Cell Identity and Function

“…Although the exact role of SAMD5 in human islets has not been described, expression of this gene is high in adult α cells but absent in adult β cells (Lawlor et al, 2017a; Segerstolpe et al, 2016; Wang et al, 2016). SAMD5 has been recently identified as a marker of peribiliary gland (PBG) cells (Yagai et al, 2017), and PBG stem cells have been documented to differentiate into glucose-responsive pancreatic islets (Cardinale et al, 2011). These data identify SAMD5 as one of the most highly connected loci in EndoC-βH1 (Figures 4C and S4B; n = 35 ChIA-PET connections between the gene and active enhancers; n = 5 interactions to other active promoters) and highlight a potential cis -regulatory hub for fetal β and islet cell development.…”

Genetic architecture and heritability of early-life telomere length in a wild passerine

“…Searching beyond the ±100 kb limits, the top marker, SNPa223513, was found closest (106 kb) to the SAMD5 (sterile alpha motif domain-containing protein 5) gene, which function is unknown, but may play a role in tumorigenesis (Sa, Lee, Hong, Kong, & Nam, 2017), cancer cell proliferation (Matsuo et al, 2014) or tumor suppression in the cytoplasm (Yagai et al, 2017). SNPa108592 is 263 kb from LRRC43 (leucine-rich repeat-containing protein 43) that belongs to a class of poorly known proteins often associated with innate immunity (Ng & Xavier, 2011).…”