Association and functional significance of genetic variants present in regulatory elements of SERPINB5 gene in gallbladder cancer

Sinha, Kirti Kumari; Vinay, J.; Parida, Suryakant; Singh, Shivaram Prasad; Dixit, Manjusha

doi:10.1016/j.gene.2021.145989

Cited by 4 publications

(2 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another study has revealed that SERPINB5, negatively mediated by Snail, disrupts the induction of EMT in tumor cells, thereby attenuating their migratory and invasive functions 29 . It has been stated that SERPINB5 genetic variation is closely related to the occurrence of GBC 30,31 . Dong's research group reported that SERPINB5 reduces the accumulation of matrix metalloproteinases MMP2 and MMP9 to decelerate the migration and invasion processes of GBC cells 32 .…”

Section: Discussionmentioning

confidence: 99%

“…29 It has been stated that SERPINB5 genetic variation is closely related to the occurrence of GBC. 30,31 Dong's research group reported that SERPINB5 reduces the accumulation of matrix metalloproteinases MMP2 and MMP9 to decelerate the migration and invasion processes of GBC cells. 32 However, the Snail.…”

Section: Studies Have Shown That Foxa2 Can Participate In Cancer Init...mentioning

confidence: 99%

See 1 more Smart Citation

FOXA2 suppresses gallbladder carcinoma cell migration, invasion, and epithelial‐mesenchymal transition by targeting SERPINB5

Hong,

Chen,

Huang

et al. 2023

Environmental Toxicology

View full text Add to dashboard Cite

BackgroundGallbladder cancer (GBC), a highly malignant gastrointestinal tumor, lacks effective therapies. Foxhead box A2 (FOXA2) is a tumor suppressor that is poorly expressed in various human malignancies. This study aimed to ascertain FOXA2 expression in GBC and its relevance to tumor metastasis, and to elucidate its regulatory mechanism with epithelial‐mesenchymal transition (EMT) as an entry point, in the hope of providing a potential therapeutic target for GBC.MethodsFOXA2 expression in GBC tissues was first detected using immunohistochemistry (IHC), followed by correlation analysis with clinicopathological characteristics and survival prognosis. Subsequently, the effects of FOXA2 on GBC cell migration and invasion, as well as EMT induction, were evaluated by scratch, Transwell, RT‐PCR, and Western blot assays, together with animal experimentation. Ultimately, mRNA sequencing was carried out to identify the key downstream target genes of FOXA2 in controlling the EMT process in GBC cells, and dual‐luciferase reporter and chromatin immunoprecipitation assays were used to determine its regulatory mechanism.ResultsFOXA2 was underexpressed in GBC tissues and inversely correlated with tumor node metastasis stage, lymph node metastasis, and poor patient prognosis. FOXA2 exerts suppressive effects on EMT and metastasis of GBC in vivo and in vitro. FOXA2 can impede GBC cell migratory and invasive functions and EMT by positively mediating serine protein kinase inhibitor B5 (SERPINB5) expression.ConclusionFOXA2 directly binds to the SERPINB5 promoter region to stimulate its transcription, thereby modulating the migration and invasion behaviors of GBC cells as well as the EMT process, which might be an effective therapeutic target against GBC.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Studies Have Shown That Foxa2 Can Participate In Cancer Init...mentioning

confidence: 99%

FOXA2 suppresses gallbladder carcinoma cell migration, invasion, and epithelial‐mesenchymal transition by targeting SERPINB5

Hong,

Chen,

Huang

et al. 2023

Environmental Toxicology

View full text Add to dashboard Cite

show abstract

Functional relevance of MMP2 promoter variants in gallbladder cancer: A case-control study in an Eastern Indian Population

Jeeyar,

Prasad Singh,

Dixit

2024

Gene

View full text Add to dashboard Cite

Gallbladder cancer-associated genetic variants rs1003349 and rs1004030 regulate MMP14 expression by altering SOX10- and MYB-binding sites

Vinay

Palo

Besra³

et al. 2023

Human Molecular Genetics

View full text Add to dashboard Cite

The pathogenesis of gallbladder cancer is complex, involving environmental and genetic risk factors. The matrix metallopeptidase 14 (MMP14) alters the tumor microenvironment and promotes tumorigenesis. In this study, we have characterized the role of the MMP14 promoter variants rs1004030 and rs1003049 in gallbladder cancer pathogenesis. Previously we have shown the association of rs1004030 and rs1003049 with GBC and allele-specific differential expression of MMP14 in GBC patients. These variants reside within the cis-Regulatory Element (CRE) with high DNase and H3K4me3 signals, suggesting an active regulatory role in MMP14 expression. The luciferase-based reporter assay showed the role of promoter variants on expression levels in two GBC cell lines. Deleting the 119 bp promoter region surrounding the variants rs1004030 and rs1003049 by CRISPR-Cas9 genome editing resulted in reduced MMP14 expression in G415 cells. Electrophoretic mobility shift assay shows the presence of risk allele ‘C’/‘G’ at rs1004030 and rs1003049 create binding sites for transcription factors SOX10 and MYB, respectively. Further, stable knockdown of these transcription factors in G415 and TGBC1TKB cells showed reduced expression of MMP14. However, in both GBC cells, ectopic expression of these transcription factors increased the expression of MMP14. Rescue of MYB and SOX10 expression levels showed a significant increase in luciferase activity only in risk allele carrying constructs. In conclusion, our study unveils a mechanistic role of the MMP14 promoter variants rs1004030 and rs1003049 in gallbladder cancer.

show abstract

Association and functional significance of genetic variants present in regulatory elements of SERPINB5 gene in gallbladder cancer

Cited by 4 publications

References 28 publications

FOXA2 suppresses gallbladder carcinoma cell migration, invasion, and epithelial‐mesenchymal transition by targeting SERPINB5

FOXA2 suppresses gallbladder carcinoma cell migration, invasion, and epithelial‐mesenchymal transition by targeting SERPINB5

Functional relevance of MMP2 promoter variants in gallbladder cancer: A case-control study in an Eastern Indian Population

Gallbladder cancer-associated genetic variants rs1003349 and rs1004030 regulate MMP14 expression by altering SOX10- and MYB-binding sites

Contact Info

Product

Resources

About