Altered expression of proteoglycan, collagen and growth factor genes in a TGF-β1 stimulated genetic risk model for musculoskeletal soft tissue injuries

Willard, Kyle; Laguette, Mary-Jessica Nancy; Rios, Leonardo Alves de Souza; Dalton, Caroline; Nel, Melissa; Prince, Sharon; Collins, Malcolm; September, Alison V.

doi:10.1016/j.jsams.2020.02.007

Cited by 10 publications

(10 citation statements)

References 27 publications

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“…TGF-β1 has a significant growth inhibitory effect on cells of epithelial origin by preventing cells from the G1-S phase in vitro, 353 , 354 and TGF-β1 expression is often reduced or absent in malignant tumors. 355 TGF-β1 can also inhibit the proliferation and induce apoptosis of GC cell lines HSC-39 and HSC-43 in vitro. 356 , 357 However, the results of another study showed that TGF-β1 protein was highly expressed in GC and increased as the differentiation degree decreased, indicating that TGF-β1 may play a role in the malignant transformation and proliferation of tumors.…”

Section: Signaling Pathways In Gastric Cancer and Therapeutic Implica...mentioning

confidence: 96%

Signaling pathways and therapeutic interventions in gastric cancer

Lei

Teng

Chen

et al. 2022

Sig Transduct Target Ther

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Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments.

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Section: Signaling Pathways In Gastric Cancer and Therapeutic Implica...mentioning

confidence: 96%

Signaling pathways and therapeutic interventions in gastric cancer

Lei

Teng

Chen

et al. 2022

Sig Transduct Target Ther

View full text Add to dashboard Cite

show abstract

“…Finally, several pathways and gene-gene interactions have been highlighted from the bioinformatic analyses and the next steps would be to explore the context of these genetic risk profiles towards a functional understanding of mechanisms underpinning risk. This can be achieved by using as an example cell culture models previously described [ 54 , 55 ]. Depending on the family of proteins being investigated (structural or ECM regulators) one could evaluate differences in the (i) mechanical properties, (ii) rates of proliferation and/or (iii) migration of the derived confluent cells from the various risk profiles.”…”

Section: Discussionmentioning

confidence: 99%

A whole genome sequencing approach to anterior cruciate ligament rupture–a twin study in two unrelated families

et al. 2022

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Predisposition to anterior cruciate ligament (ACL) rupture is multi-factorial, with variation in the genome considered a key intrinsic risk factor. Most implicated loci have been identified from candidate gene-based approach using case-control association settings. Here, we leverage a hypothesis-free whole genome sequencing in two two unrelated families (Family A and B) each with twins with a history of recurrent ACL ruptures acquired playing rugby as their primary sport, aimed to elucidate biologically relevant function-altering variants and genetic modifiers in ACL rupture. Family A monozygotic twin males (Twin 1 and Twin 2) both sustained two unilateral non-contact ACL ruptures of the right limb while playing club level touch rugby. Their male sibling sustained a bilateral non-contact ACL rupture while playing rugby union was also recruited. The father had sustained a unilateral non-contact ACL rupture on the right limb while playing professional amateur level football and mother who had participated in dancing for over 10 years at a social level, with no previous ligament or tendon injuries were both recruited. Family B monozygotic twin males (Twin 3 and Twin 4) were recruited with Twin 3 who had sustained a unilateral non-contact ACL rupture of the right limb and Twin 4 sustained three non-contact ACL ruptures (two in right limb and one in left limb), both while playing provincial level rugby union. Their female sibling participated in karate and swimming activities; and mother in hockey (4 years) horse riding (15 years) and swimming, had both reported no previous history of ligament or tendon injury. Variants with potential deleterious, loss-of-function and pathogenic effects were prioritised. Identity by descent, molecular dynamic simulation and functional partner analyses were conducted. We identified, in all nine affected individuals, including twin sets, non-synonymous SNPs in three genes: COL12A1 and CATSPER2, and KCNJ12 that are commonly enriched for deleterious, loss-of-function mutations, and their dysfunctions are known to be involved in the development of chronic pain, and represent key therapeutic targets. Notably, using Identity By Decent (IBD) analyses a long shared identical sequence interval which included the LINC01250 gene, around the telomeric region of chromosome 2p25.3, was common between affected twins in both families, and an affected brother’. Overall gene sets were enriched in pathways relevant to ACL pathophysiology, including complement/coagulation cascades (p = 3.0e-7), purine metabolism (p = 6.0e-7) and mismatch repair (p = 6.9e-5) pathways. Highlighted, is that this study fills an important gap in knowledge by using a WGS approach, focusing on potential deleterious variants in two unrelated families with a historical record of ACL rupture; and providing new insights into the pathophysiology of ACL, by identifying gene sets that contribute to variability in ACL risk.

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“…We therefore hypothesize that the “ Goldilocks affect ” is still plausible 40 whereby a finely tuned homeostatic feedback regulation of turnover of ligament ECM components is required for optimal repair responses. More recently, Willard et al 41 and Suijkerbuijk et al 24 have shown functional evidence linking a genetic contribution to the expression of ECM components in a susceptibility model.…”

Section: Discussionmentioning

confidence: 99%

Investigation of multiple populations highlight VEGFA polymorphisms to modulate anterior cruciate ligament injury

Feldmann

Rahim

Suijkerbuijk

et al. 2021

Journal Orthopaedic Research

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Polymorphisms in VEGFA and KDR encoding proteins have been associated with anterior cruciate ligament (ACL) injury risk. We leveraged a collective sample from Sweden, Poland, and Australia to investigate the association of functional polymorphisms in VEGFA and KDR with susceptibility to ACL injury risk. Using a case–control genetic association approach, polymorphisms in VEGFA and KDR were genotyped and haplotypes inferred from 765 controls, and 912 cases clinically diagnosed with ACL rupture. For VEGFA, there was a significant overrepresentation of the rs2010963 CC genotype (p = 0.0001, false discovery rate [FDR]: p = 0.001, odds ratio [OR]: 2.16, 95% confidence interval [CI]: 1.47–3.19) in the combined ACL group (18%) compared to the combined control group (11%). The VEGFA (rs699947 C/A, rs1570360 G/A, rs2010963 G/C) A‐A‐G haplotype was significantly (p = 0.010, OR: 0.85, 95% CI: 0.69–1.05) underrepresented in the combined ACL group (23%) compared to the combined control group (28%). In addition, the A‐G‐G construct was significantly (p = 0.036, OR: 0.81, 95% CI: 0.64–1.02) underrepresented in the combined ACL group (12%) compared to the combined CON group (16%). Our findings support the association of the VEGFA rs2010963 CC genotype with increased risk and (ii) the VEGFA A‐A‐G haplotype with a reduced risk, and are in alignment with the a priori hypothesis. Collectively identifying a genetic interval within VEGFA to be implicated in ACL risk modulation and highlight further the importance of vascular regulation in ligament biology.

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Altered expression of proteoglycan, collagen and growth factor genes in a TGF-β1 stimulated genetic risk model for musculoskeletal soft tissue injuries

Cited by 10 publications

References 27 publications

Signaling pathways and therapeutic interventions in gastric cancer

Signaling pathways and therapeutic interventions in gastric cancer

A whole genome sequencing approach to anterior cruciate ligament rupture–a twin study in two unrelated families

Investigation of multiple populations highlight VEGFA polymorphisms to modulate anterior cruciate ligament injury

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