p53‑p72‑Δ225‑331‑V31I identified in a cholangiocarcinoma cell line promotes migration and invasiveness via the downregulation of claudin‑1 expression and the activation of Cdc42

Puetkasichonpasutha, Janpen; Suthiphongchai, Tuangporn

doi:10.3892/or.2020.7827

Cited by 4 publications

(3 citation statements)

References 52 publications

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“…More evidence shows that nonsense mutations play significant roles in tumorigenesis in several cancer types, including breast, lung, gastric, and pancreatic cancer and so on ( 8 – 11 ). In CCA, a nonsense mutation of p53 promoted cell proliferation and migration, and the nonsense mutation in LGR4 was associated with an increased risk of carcinogenesis ( 12 , 13 ). Through whole-exome sequencing of 67 CCA tissues, we identified new mutated genes in CCA, including MACF1, METTL14, ROBO1, and so on.…”

Section: Introductionmentioning

confidence: 99%

ROBO1 p.E280* Loses the Inhibitory Effects on the Proliferation and Angiogenesis of Wild-Type ROBO1 in Cholangiocarcinoma by Interrupting SLIT2 Signal

et al. 2022

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BackgroundCholangiocarcinoma (CCA) remains one of the most lethal malignancies with an increasing incidence globally. Through whole-exome sequencing of 67 CCA tissues, we identified new mutated genes in CCA, including MACF1, METTL14, ROBO1, and so on. The study was designed to explore the effects and mechanism of ROBO1 wild type (ROBO1WT) and ROBO1E280* mutation on the progression of CCA.MethodsWhole-exome sequencing was performed to identify novel mutations in CCAs. In vitro and in vivo experiments were used to examine the function and mechanism of ROBO1WT and ROBO1E280* in cholangiocarcinoma. A tissue microarray including 190 CCA patients and subsequent analyses were performed to indicate the clinical significance of ROBO1.ResultsThrough whole-exome sequencing, we identified a novel CCA-related mutation, ROBO1E280*. ROBO1 was downregulated in CCA tissues, and the downregulation of ROBO1 was significantly correlated with poor prognosis. ROBO1WT suppressed the proliferation and angiogenesis of CCA in vitro and in vivo, while ROBO1E280* lost the inhibitory effects. Mechanically, ROBO1E280* translocated from the cytomembrane to the cytoplasm and interrupted the interaction between SLIT2 and ROBO1. We identified OLFML3 as a potential target of ROBO1 by conducting RNA-Seq assays. OLFML3 expression was downregulated by ROBO1WT and recovered by ROBO1E280*. Functionally, the silence of OLFML3 inhibited CCA proliferation and angiogenesis and was sufficient to repress the loss-of-function role of ROBO1E280*.ConclusionsThese results suggest that ROBO1 may act as a tumor suppressor and potential prognostic marker for CCA. ROBO1E280* mutation is a loss-of-function mutation, and it might serve as a candidate therapeutic target for CCA patients.

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Section: Introductionmentioning

confidence: 99%

ROBO1 p.E280* Loses the Inhibitory Effects on the Proliferation and Angiogenesis of Wild-Type ROBO1 in Cholangiocarcinoma by Interrupting SLIT2 Signal

et al. 2022

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“…38,43 Hence, a mutation in this residue would not significantly affect the transactivation potential of TAD1 unless it occurs with other mutations, leading to premature incapacitation of p53 activity. 39,40,44,45 Particularly, there is truncated activity if V31I occurs with mutations and post-translational modifications (i.e., protein phosphorylation) in the key residues that directly interact with proteins, namely, F19, L22, W23, L25, L26. 40,41,43 Therefore, it is possible that there are other mutations within the TP53 gene that predisposed the development of choledochal cyst among the patients in this study.…”

Section: Tp53 Rs201753350 Germline Variant Is More Likely Benignmentioning

confidence: 99%

Association of TP53 Germline Variant and Choledochal Cyst among Clinically Diagnosed Filipino Pediatric Patients

2024

Acta Med Philipp

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Background and Objective. Choledochal cysts (CC) are rare congenital, cystic dilations of the biliary tree occurring predominantly in Asian populations and in females. Patients are usually children presenting with any of the following: abdominal pain, palpable abdominal mass, and jaundice. Its congenital nature hints at a potential genetic cause. A possible causal gene is TP53, a tumor suppressor with a germline variant called rs201753350 (c.91G>A) that changed from a G allele to an A allele, decreasing the cell proliferation suppressing activity of its functional protein.Currently, there is no information on the TP53 rs201753350 germline variant available for the Filipino population. This study determined the prevalence of rs201753350 and the association between the functional G allele, the rs201753350 germline variant A allele, and the occurrence of CCs in Filipino pediatric patients in a tertiary government hospital.Methods. Genomic DNA was extracted from blood samples of pediatric patients clinically diagnosed with CC. Controls were DNA samples collected from a previous study. The samples underwent PCR, electrophoresis, and sequencing. Results.A total of 109 participants (22 cases and 87 controls) were included in the study. The A allele (22.94%) occurs at a lower frequency than the G allele (77.06%) among both cases and controls. More individuals have a homozygous G/G genotype (54.13%) than a heterozygous A/G genotype (45.87%) while the homozygous A/A genotype was not observed. The estimated risk of choledochal cyst occurrence is significantly lower in individuals with the A allele (PR: 0.08, 95% CI: 0.01 -0.55) and the A/G genotype (PR: 0.06, 95% CI: 0.01 -0.40). Conclusion.There is no significant evidence to suggest an association between the TP53 rs201753350 germline variant and the occurrence of choledochal cysts in Filipinos. It is recommended that other mutations within and beyond the TP53 gene be investigated for possible associations with choledochal cyst occurrence.

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“…This was associated with a decrease in CLDN1 expression. It was also noted to lack anti-growth functions and instead enhanced migration and invasiveness [172].…”

Section: Role Of Claudins In Cancer Metastasismentioning

confidence: 99%

Claudins in Cancer: A Current and Future Therapeutic Target

Hana,

Thaw Dar,

Galo Venegas

et al. 2024

IJMS

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Claudins are a family of 27 proteins that have an important role in the formation of tight junctions. They also have an important function in ion exchange, cell mobility, and the epithelial-to-mesenchymal transition, the latter being very important in cancer invasion and metastasis. Therapeutic targeting of claudins has been investigated to improve cancer outcomes. Recent evidence shows improved outcomes when combining monoclonal antibodies against claudin 18.2 with chemotherapy for patients with gastroesophageal junction cancer. Currently, chimeric antigen receptor T-cells targeting claudin 18 are under investigation. In this review, we will discuss the major functions of claudins, their distribution in the normal as well as cancerous tissues, and their effect in cancer metastasis, with a special focus on the therapeutic targeting of claudins to improve cancer outcomes.

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p53‑p72‑Δ225‑331‑V31I identified in a cholangiocarcinoma cell line promotes migration and invasiveness via the downregulation of claudin‑1 expression and the activation of Cdc42

Cited by 4 publications

References 52 publications

ROBO1 p.E280* Loses the Inhibitory Effects on the Proliferation and Angiogenesis of Wild-Type ROBO1 in Cholangiocarcinoma by Interrupting SLIT2 Signal

ROBO1 p.E280* Loses the Inhibitory Effects on the Proliferation and Angiogenesis of Wild-Type ROBO1 in Cholangiocarcinoma by Interrupting SLIT2 Signal

Association of TP53 Germline Variant and Choledochal Cyst among Clinically Diagnosed Filipino Pediatric Patients

Claudins in Cancer: A Current and Future Therapeutic Target

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