Identification of low-density lipoprotein receptor class A domain containing 4 (LDLRAD4) as a prognostic indicator in primary gastrointestinal stromal tumors

Xie, Wei; Xiao, He; Luo, Jia; Zhao, Limei; Jin, Feng; Ma, Jun; Li, Jian; Xiong, Kai; Chen, Chuan; Wang, Ge

doi:10.1016/j.currproblcancer.2020.100593

Cited by 5 publications

(4 citation statements)

References 39 publications

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“…Prior studies have demonstrated an association of genetic variants in LDLRAD4 with schizophrenia bipolar disorder ( 24 , 25 ), and a low-frequency variant (rs8096897) in this gene showed evidence of association with systolic blood pressure ( 26 ). This gene has also been described as a prognostic indicator in primary gastrointestinal stromal tumors ( 27 ). LDLRAD4 , also known as C18orf1 , is involved in the downregulation of transforming growth factor-β (TGF-β) by interacting with downstream effectors SMAD2 (SMAD Family Member) and SMAD3 via its SIM (SIM BHLH Transcription Factor) domain ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic and clinical determinants of abdominal aortic diameter: genome-wide association studies, exome array data and Mendelian randomization study

Portilla‐Fernandez

Klarin

Hwang

et al. 2022

Human Molecular Genetics

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Progressive dilation of the infrarenal aortic diameter is a consequence of the ageing process and is considered the main determinant of Abdominal Aortic Aneurysm (AAA). We aimed to investigate the genetic and clinical determinants of abdominal aortic diameter (AAD). We conducted a meta-analysis of genome-wide association studies in ten cohorts (n = 13 542) imputed to the 1000 Genome Project reference panel including 12 815 subjects in the discovery phase and 727 subjects (PBIO) as replication. Maximum anterior–posterior diameter of the infrarenal aorta was used as AAD. We also included exome array data (n = 14 480) from seven epidemiologic studies. Single-variant and gene-based associations were done using SeqMeta package. A Mendelian randomization analysis was applied to investigate the causal effect of a number of clinical risk factors on AAD. In GWAS on AAD, rs74448815 in the intronic region of LDLRAD4 reached genome-wide significance (beta = −0.02, SE = 0.004, p-value = 2.10 × 10−8). The association replicated in the PBIO1 cohort (p-value = 8.19 × 10−4). In exome-array single-variant analysis (p-value threshold = 9 × 10−7), the lowest p-value was found for rs239259 located in SLC22A20 (beta = 0.007, p-value =1.2 × 10−5). In the gene-based analysis (p-value threshold = 1.85 × 10−6), PCSK5 showed an association with AAD (p-value = 8.03 × 10−7). Furthermore, in Mendelian randomization analyses, we found evidence for genetic association of pulse pressure (beta = −0.003, p-value = 0.02), triglycerides (beta = −0.16, p-value = 0.008) and height (beta = 0.03, p-value<0.0001), known risk factors for AAA, consistent with a causal association with AAD. Our findings point to new biology as well as highlighting gene regions in mechanisms that have previously been implicated in the genetics of other vascular diseases.

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Section: Discussionmentioning

confidence: 99%

Genetic and clinical determinants of abdominal aortic diameter: genome-wide association studies, exome array data and Mendelian randomization study

Portilla‐Fernandez

Klarin

Hwang

et al. 2022

Human Molecular Genetics

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“…In SDH-deficient GISTs, mitotic count does not predict tumor behavior[ 63 ]. Therefore, at the basic research level, an attempt has been made to predict the risk of GIST recurrence by measuring gene expression related to DNA methylation; this has been shown to be an effective predictor[ 64 ].…”

Section: Risk Assessment and Adjuvant Therapymentioning

confidence: 99%

Current treatment strategies and future perspectives for gastrointestinal stromal tumors

Sugiyama¹,

Sasaki²,

Kouyama³

et al. 2022

WJGP

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Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that originate from the gastrointestinal tract, mostly from the stomach. GISTs are derived from the myenteric interstitial cells of Cajal and are caused by several mutations in the c-kit and platelet-derived growth factor receptor genes. Clinically, GISTs are detected by endoscopic and imaging findings and are diagnosed by immunostaining. Surgery is the first line of treatment, and if the tumor is relatively small, minimally invasive surgery such as laparoscopy is performed. In recent years, neoadjuvant therapy has been administered to patients with GISTs that are suspected of having a large size or infiltration to other organs. Postoperative adjuvant imatinib is the standard therapy for high-risk GISTs. It is important to assess the risk of recurrence after GIST resection. However, the effect of tyrosine kinase inhibitor use will vary by the mutation of c-kit genes and the site of mutation. Furthermore, information regarding gene mutation is indispensable when considering the treatment policy for recurrent GISTs. This article reviews the clinicopathological characteristics of GISTs along with the minimally invasive and multidisciplinary treatment options available for these tumors. The future perspectives for diagnostic and treatment approaches for these tumors have also been discussed.

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“…Low-density lipoprotein receptor class a domain containing 4 (LDLRAD4), also known as C18ORF1, is related to schizophrenia 26,27 and tumorigenesis in hepatic cancer cells, 28 and serve as a prognostic marker of gastrointestinal stromal tumors. 29 LDLRAD4 forms a homomeric complex that binds with Smad2/3 through the Smad-interacting motif domain. 30 This complex inhibits the activation of Smad2/3 and eventually blocks TGF-β signaling, which plays a crucial role in organ fibrosis through Smad and non-Smad pathways.…”

mentioning

confidence: 99%

“…Low-density lipoprotein receptor class a domain containing 4 (LDLRAD4), also known as C18ORF1, is related to schizophrenia , and tumorigenesis in hepatic cancer cells, and serve as a prognostic marker of gastrointestinal stromal tumors . LDLRAD4 forms a homomeric complex that binds with Smad2/3 through the Smad-interacting motif domain .…”

mentioning

confidence: 99%

Novel Peptide DR3penA as a Low-Toxicity Antirenal Fibrosis Agent by Suppressing the TGF-β1/miR-212-5p/Low-Density Lipoprotein Receptor Class a Domain Containing 4/Smad Axis

Deng,

Zhang,

Zhang

et al. 2024

ACS Pharmacol. Transl. Sci.

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Renal fibrosis is a complex pathological process that contributes to the development of chronic kidney disease due to various risk factors. Conservative treatment to curb progression without dialysis or renal transplantation is widely applicable, but its effectiveness is limited. Here, the inhibitory effect of the novel peptide DR3penA (DHα-(4-pentenyl)-AlaNPQIR-NH 2 ), which was developed by our group, on renal fibrosis was assessed in cells and mice with established fibrosis and fibrosis triggered by transforming growth factor-β1 (TGF-β1), unilateral ureteral obstruction, and repeated low-dose cisplatin. DR3penA preserved renal function and ameliorated renal fibrosis at a dose approximately 100 times lower than that of captopril, which is currently used in the clinic. DR3penA also significantly reduced existing fibrosis and showed similar efficacy after subcutaneous or intraperitoneal injection. Mechanistically, DR3penA repressed TGF-β1 signaling via miR-212-5p targeting of low-density lipoprotein receptor class a domain containing 4, which interacts with Smad2/3. In addition to having good pharmacological effects, DR3penA could preferentially target injured kidneys and exhibited low toxicity in acute and chronic toxicity experiments. These results unveil the advantages of DR3penA regarding efficacy and toxicity, making it a potential candidate compound for renal fibrosis therapy.

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Identification of low-density lipoprotein receptor class A domain containing 4 (LDLRAD4) as a prognostic indicator in primary gastrointestinal stromal tumors

Cited by 5 publications

References 39 publications

Genetic and clinical determinants of abdominal aortic diameter: genome-wide association studies, exome array data and Mendelian randomization study

Genetic and clinical determinants of abdominal aortic diameter: genome-wide association studies, exome array data and Mendelian randomization study

Current treatment strategies and future perspectives for gastrointestinal stromal tumors

Novel Peptide DR3penA as a Low-Toxicity Antirenal Fibrosis Agent by Suppressing the TGF-β1/miR-212-5p/Low-Density Lipoprotein Receptor Class a Domain Containing 4/Smad Axis

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