Implications of CLSPN Variants in Cellular Function and Susceptibility to Cancer

Azenha, Diana; Pérez, Santiago Hernández; Martín, Yusé; Viegas, Marta S.; Martins, Alexandra; Lopes, María Celeste; Lam, Eric W.‐F.; Freire, Raimundo; Martins, Teresa

doi:10.3390/cancers12092396

Cited by 5 publications

(7 citation statements)

References 66 publications

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“…To thoroughly understand the features of CLSPN, we further explored its alterations utilizing cBioPortal database. Among these alterations, we observed missense mutation as the commonest type, while inframe mutation was the rarest, which was consistent with the research of other scholars [ 44 , 45 ]. Besides, our results revealed that the truncate mutation of R1139*/Q site in CLSPN had the highest frequency, which had never been proved by basic experiments before.…”

Section: Discussionsupporting

confidence: 91%

A multi-omics analysis reveals CLSPN is associated with prognosis, immune microenvironment and drug resistance in cancers

et al. 2023

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Background Immunotherapy is effective only in limited patients. It is urgent to discover a novel biomarker to predict immune cells infiltration status and immunotherapy response of different cancers. CLSPN has been reported to play a pivotal role in various biological processes. However, a comprehensive analysis of CLSPN in cancers has not been conducted. Methods To show the whole picture of CLSPN in cancers, a pan-cancer analysis was conducted in 9125 tumor samples across 33 cancer types by integrating transcriptomic, epigenomic and pharmacogenomics data. Moreover, the role of CLSPN in cancer was validated by CCK-8, EDU, colony formation and flow cytometry in vitro and tumor cell derived xenograft model in vivo. Results CLSPN expression was generally upregulated in most cancer types and was significantly associated with prognosis in different tumor samples. Moreover, elevated CLSPN expression was closely correlated with immune cells infiltration, TMB (tumor mutational burden), MSI (microsatellite instability), MMR (mismatch repair), DNA methylation and stemness score across 33 cancer types. Enrichment analysis of functional genes revealed that CLSPN participated in the regulation of numerous signaling pathways involved in cell cycle and inflammatory response. The expression of CLSPN in LUAD patients were further analyzed at the single-cell level. Knockdown CLSPN significantly inhibited cancer cell proliferation and cell cycle related cyclin-dependent kinase (CDK) family and Cyclin family expression in LUAD (lung adenocarcinoma) both in vitro and in vivo experiments. Finally, we conducted structure-based virtual screening by modelling the structure of CHK1 kinase domain and Claspin phosphopeptide complex. The top five hit compounds were screened and validated by molecular docking and Connectivity Map (CMap) analysis. Conclusion Our multi-omics analysis offers a systematic understanding of the roles of CLSPN in pan-cancer and provides a potential target for future cancer treatment.

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Section: Discussionsupporting

confidence: 91%

A multi-omics analysis reveals CLSPN is associated with prognosis, immune microenvironment and drug resistance in cancers

et al. 2023

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“…Furthermore, SNPs in these regions can alter gene expression or alter gene-molecule interactions leading to complex diseases [16]. A CLSPN mutation c.1574A>G has been demonstrated to reduce CLSPN expression and activate Chk1, which may affect the CLSPN structure and function in breast cancer [25]. There is evidence that CLSPN, which has been found to express the I783S missense mutation that inhibits its ability to mediate Chk1 phosphorylation after DNA damage, may be associated with tumorigenesis [24].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, elevated expression of CLSPN is closely related to the induction of immune cell infiltration, tumor mutation burden, microsatellite instability, mismatch repair, and DNA methylation in various cancer types [23]. In recent years, researchers have begun to study the role of the CLSPN gene in cancer development, specifically after finding high levels of CLSPN in cancers as diverse as breast, ovarian, cervical, glioma, non-small cell lung cancer and renal cell carcinoma [24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

“…CLSPN gene polymorphism refers to the DNA sequence variations or mutations of the CLSPN gene that exist within a population. These gene polymorphisms may impact the expression, function, or regulation of the CLSPN gene, thereby exerting significant effects on cancer occurrence and progression [25]. However, the mechanisms leading to OSCC occurrence and single nucleotide polymorphisms (SNPs) remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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The Interaction between CLSPN Gene Polymorphisms and Alcohol Consumption Contributes to Oral Cancer Progression

Hsieh,

Lo,

et al. 2024

IJMS

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Most disease single nucleotide polymorphisms (SNPs) are regulatory and approximately half of heritability is occupied by the top 1% of genes, with the gene-level structure varying with the number of variants associated with the most common alleles. Cancer occurrence and progression are significantly affected by Claspin (CLSPN) gene polymorphism present in the population, which alters the expression, function, and regulation of the gene. CLSPN genotypes are associated with oral cancer, but the literature on this association is limited. As a result, the goal of this study is to investigate the correlation between CLSPN genotypes and oral cancers’ development. This study will explore the presence of four CLSPN SNPs including rs12058760, rs16822339, rs535638 and rs7520495 gene polymorphisms, and analyze the expression of these genes in 304 cancer-free controls and 402 oral squamous cell carcinoma (OSCC) cases. Attempts have been made to obtain insight into the role of CLSPN gene polymorphisms in oral cancer through the analysis of this study. We demonstrated that the OSCC risk of individuals with four CLSPN SNPs relative to the wild type did not differ significantly from that of the wild type when the polymorphisms are analyzed according to individual habits. We further studied the mechanism by which CLSPN polymorphisms affect the progression of clinicopathological features in OSCC patients. The results of the degree of cell differentiation showed that compared with patients of rs7520495 SNP carrying the CC genotype, the incidence of poor cell differentiation in patients carrying the CC + GG genotype was higher (AOR: 1.998-fold; 95% CI, 1.127–3.545; p = 0.018). In particular, patients with the G genotype of rs7520495 had increased poor cell differentiation compared with patients with the C genotype (AOR: 4.736-fold; 95% CI, 1.306–17.178; p = 0.018), especially in the drinking group. On the basis of our analysis of the Cancer Genome Atlas dataset, we found that higher CLSPN levels were associated with poorer cell differentiation in oral cancers. In this study, we provide the first evidence showing that CLSPN SNPs contribute to oral cancer. Whether or not rs7520495 can be used as a confirmatory factor in the future is uncertain, but it seems likely that it can be used as an important factor in predicting recurrence, response to treatment and medication toxicity to patients with oral cancer.

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“…Therefore, it is urgent to establish an understanding of the pathogenesis of HCC and to seek effective therapeutic targets. CLSPN, an essential molecule of the S-phase checkpoint in DNA replication stress, has been proven to be involved in the process of cancers (10,21), but its roles in HCC remain ambiguous.…”

Section: Discussionmentioning

confidence: 99%

Demystification of CLSPN multiple potentialities in hepatocellular carcinoma: insight into individualized diagnosis and precision therapeutics

Shi

Wang

Niu

et al. 2023

Preprint

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CLSPN, an essential molecule of the S-phase checkpoint in DNA replication stress, have not been elucidated in hepatocellular carcinoma (HCC). In this study, we firstly discovered and systematically verified CLSPN expression using RT-qPCR and western blotting assay, and its high expression was an independent prognostic factor in HCC. Patients with CLSPN low-expression had higher infiltration levels of T cell CD4 + memory resting, monocyte, mast cell activated, dryness index and lower immune response in HCC. Then, CLSPN silencing inhibited the proliferation, migration, invasion and cell cycle progression of HCC cells proved by CCK-8, transwell and cell cycle assay. We established a key lncRNA PSMA3-AS1/hsa-miR-101-3p/CLSPN regulator axis in HCC. Furthermore, CLSPN-mediated ubiquitination or deubiquitination may regulate post-transcriptional modifications in HCC. The emerging CLSPN potentialities might be mediated by the β-catenin-mediated Wnt signaling pathway. In addition, we detected CLSPN interaction protein profile, which further confirmed CLSPN involved in posttranscriptional modification, protein turnover, and biogenesis locating in cytoplasm, secreted, and mitochondrion. Therefore, it was the first time to discover and verify expression, prognosis, immunotherapy, RNAs regulator, posttranscriptional modification, and molecular mechanisms of CLSPN in HCC. These novel insights might accelerate the process of individualized diagnosis and precision therapeutics for patients with HCC.

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Implications of CLSPN Variants in Cellular Function and Susceptibility to Cancer

Cited by 5 publications

References 66 publications

A multi-omics analysis reveals CLSPN is associated with prognosis, immune microenvironment and drug resistance in cancers

A multi-omics analysis reveals CLSPN is associated with prognosis, immune microenvironment and drug resistance in cancers

The Interaction between CLSPN Gene Polymorphisms and Alcohol Consumption Contributes to Oral Cancer Progression

Demystification of CLSPN multiple potentialities in hepatocellular carcinoma: insight into individualized diagnosis and precision therapeutics

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