Protocadherin γ A3 is expressed in follicular lymphoma irrespective of BCL2 status and is associated with tumor cell growth

Abstract

Protocadherin genes (PCDHs) have been suggested to act as tumor suppressor genes in various tumor types. Previous studies have demonstrated the upregulation of certain PCDH-γ subfamily genes in nodal and duodenal follicular lymphoma (FL) using gene expression analyses. However, the mechanisms and associated molecular function of PCDH-γ subfamily gene upregulation in FL remain to be elucidated. The present study examined the expression of PCDHGA3, an upregulated PCDH-γ gene subfamily member, in B-cell lymphoma 2 (BCL2)-positive and -negative FL, and evaluated its association with tumor cell proliferation in an FL-derived cell line. Immunohistochemical analysis demonstrated that the majority of FL grade 1–2 samples (19/20; 95%) and over half of grade 3A FL samples (5/9; 56%) were PCDHGA3-positive, whereas only 1/17 reactive lymphoid hyperplasia samples was positive. Notably, this positivity was widely observed in samples of BCL2-negative FL (13/15; 87%) and FL with diffuse area (10/10; 100%). The FL-derived cell line FL18 exhibited strong PCDHGA3 expression, similar to the patient samples, and its proliferation was suppressed by PCDHGA3 gene knockdown. Genes expressed concomitantly with PCDHGA3 were selected from gene expression data, and TNFRSF6B, a member of the tumor necrosis factor receptor superfamily, was among the top five most strongly correlated genes. Coexpression of TNFRSF6B and PCDHGA3 was observed immunohistochemically in FL18 cells, suggesting potential cooperation in tumor cell maintenance. In conclusion, the results of the present study indicated that PCDHGA3 was expressed in FL irrespective of BCL2 status and grading and was associated with cell proliferation. Further studies involving molecular genetic analyses are required to elucidate the mechanisms underlying the activity of PCDHGA3 in FL.

DNA methylation associated with healthy aging of elderly twins

“…DNA methylation levels at the 5′ regions of clustered PCDHA genes inversely correlate with gene expression levels, and 5-azacytidine treatment induces expression of silent PCDHA genes (Kawaguchi et al 2008). Hypermethylation is also associated with reduced expression of PCDHB and PCDHG genes (Dallosso et al 2009), and reduced or deregulated protocadherin expression is associated with various neurological, psychiatric, and cardiovascular disorders, and tumor growth (Dallosso et al 2009;Ortega et al 2016;Zhang et al 2016;El Hajj et al 2017). Interestingly, hypermethylation at the promoter regions of the Fig.…”

Peer Review #3 of "Identification of hub genes and molecular mechanisms in infant acute lymphoblastic leukemia with MLL gene rearrangement (v0.2)"

“…PCDHGA, PCDHGB, PCDHGC) may contribute to cell migration and invasion. Previous studies have confirmed that PCDH genes were involved in tumorigenesis and metastasis of gastric cancer, follicular lymphoma and non-small cell lung cancer (Mukai et al, 2017;Zhang et al, 2016;Zhou et al, 2017), although other studies have found that PCDH genes were implicated in tumor suppression (Chen et al, 2017;Weng et al, 2018). However, the role of PCDH genes in MLL-R ALL is currently unclear.…”

Identification of hub genes and molecular mechanisms in infant acute lymphoblastic leukemia withMLLgene rearrangement

“…Homophilic cell adhesion, mediated by the up-regulation of protocadherin ( PCDH ) γ subfamily of genes (e.g., PCDHGA , PCDHGB , PCDHGC ) may contribute to cell migration and invasion. Previous studies have confirmed that PCDH genes were involved in tumorigenesis and metastasis of gastric cancer, follicular lymphoma and non-small cell lung cancer (Mukai et al, 2017; Zhang et al, 2016; Zhou et al, 2017), although other studies have found that PCDH genes were implicated in tumor suppression (Chen et al, 2017; Weng et al, 2018). However, the role of PCDH genes in MLL -R ALL is currently unclear.…”