Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer

Abstract

BackgroundTransforming growth factor, beta (TGFB) signal is considered to be a tumor suppressive pathway based on the frequent genomic deletion of the SMAD4 gene in pancreatic cancer (PC); however; the role of the activin signal, which also belongs to the TGFB superfamily, remains largely unclear.Methods and resultsWe found a homozygous deletion of the activin A receptor, type IB (ACVR1B) gene in 2 out of 8 PC cell lines using array-comparative genomic hybridization, and the absence of ACVR1B mRNA and protein expression was confirmed in these 2 cell lines. Activin A stimulation inhibited cellular growth and increased the phosphorylation level of SMAD2 and the expression level of p21CIP1/WAF1 in the Sui66 cell line (wild-type ACVR1B and SMAD4 genes) but not in the Sui68 cell line (homozygous deletion of ACVR1B gene). Stable ACVR1B-knockdown using short hairpin RNA cancelled the effects of activin A on the cellular growth of the PC cell lines. In addition, ACVR1B-knockdown significantly enhanced the cellular growth and colony formation abilities, compared with controls. In a xenograft study, ACVR1B-knockdown resulted in a significantly elevated level of tumorigenesis and a larger tumor volume, compared with the control. Furthermore, in clinical samples, 6 of the 29 PC samples (20.7%) carried a deletion of the ACVR1B gene, while 10 of the 29 samples (34.5%) carried a deletion of the SMAD4 gene. Of note, 5 of the 6 samples with a deletion of the ACVR1B gene also had a deletion of the SMAD4 gene.ConclusionWe identified a homozygous deletion of the ACVR1B gene in PC cell lines and clinical samples and proposed that the deletion of the ACVR1B gene may mediate an aggressive cancer phenotype in PC. Our findings provide novel insight into the role of the activin signal in PC.

Esophageal squamous cell carcinoma invasion is inhibited by Activin A in ACVRIB-positive cells

“…The mutations identified are similar to the well-characterized frameshift mutations in TGFBR2 [62]. Inactivation of ACVRIB so far has only been identified in pancreatic cancer as a consequence of a somatic mutation [63], and homologous deletion is associated with an aggressive phenotype in pancreatic cancer [64]. Based on the 120 esophageal squamous tumor tissues we analyzed in this study, we found that ACVRIB can also be lost in ESCC.…”

The systemic activin response to pancreatic cancer: implications for effective cancer cachexia therapy

“…RNAseq data from TCGA showed a positive association of only tumour activin A expression on mortality and not for genes encoding Inhibin-alpha, follistatin and related proteins, activin B, or receptors ACVR1B, ACVR1C, ACVR2A, and ACVR2B (not shown), despite empirical evidence of certain of these receptors influencing tumour phenotype. [60][61][62][63] Moreover, RNA expression of the closely related proteins, myostatin, and GDF-11 in tumours was actually associated with reduced mortality, despite their ability to induce systemic wasting. 64,65 These results suggest highly context- specific roles of these factors in PDAC disease progression and mortality.…”

Methyl-CpG-binding domain 3 inhibits epithelial–mesenchymal transition in pancreatic cancer cells via TGF-β/Smad signalling

“…Previous study has demonstrated that TGF- β /Smad signalling is operational in pancreatic cancer (Togashi et al , 2014). When TGF- β is activated, Smad2 is phosphorylated and undergoes dimerisation with Smad3, thus allowing its translocation into nucleus in cancer cells, promoting the EMT progress (Liu et al , 2012; Liu et al , 2015).…”