Obscurin: A multitasking giant in the fight against cancer

Guardia, Talia; Eason, Matthew G.; Kontrogianni‐Konstantopoulos, Aikaterini

doi:10.1016/j.bbcan.2021.188567

Cited by 11 publications

(16 citation statements)

References 95 publications

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“…The high-risk group had an increased mutation rate for TP53, LRP1B, and OBSCN. A previous study showed that OBSCN is an effective tumor suppressor in various cancers (Guardia et al, 2021). It is also known that TP53 mutation frequency is higher in cancers with increased malignancy.…”

Section: Discussionmentioning

confidence: 96%

A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response

Yang

Wang

et al. 2023

Front. Pharmacol.

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Background: Intracellular copper homeostasis requires a complex system. It has shown considerable prospects for intervening in the tumor microenvironment (TME) by regulating copper homeostasis and provoking cuproptosis. Their relationship with hepatocellular carcinoma (HCC) remains elusive.Methods: In TCGA and ICGC datasets, LASSO and multivariate Cox regression were applied to obtain the signature on the basis of genes associated with copper homeostasis and cuproptosis. Bioinformatic tools were utilized to reveal if the signature was correlated with HCC characteristics. Single-cell RNA sequencing data analysis identified differences in tumor and T cells’ pathway activity and intercellular communication of immune-related cells. Real-time qPCR analysis was conducted to measure the genes’ expression in HCC and adjacent normal tissue from 21 patients. CCK8 assay, scratch assay, transwell, and colony formation were conducted to reveal the effect of genes on in vitro cell proliferation, invasion, migration, and colony formation.Results: We constructed a five-gene scoring system in relation to copper homeostasis and cuproptosis. The high-risk score indicated poor clinical prognosis, enhanced tumor malignancy, and immune-suppressive tumor microenvironment. The T cell activity was markedly reduced in high-risk single-cell samples. The high-risk HCC patients had a better expectation of ICB response and reactivity to anti-PD-1 therapy. A total of 156 drugs were identified as potential signature-related drugs for HCC treatment, and most were sensitive to high-risk patients. Novel ligand-receptor pairs such as FASLG, CCL, CD40, IL2, and IFN-Ⅱ signaling pathways were revealed as cellular communication bridges, which may cause differences in TME and immune function. All crucial genes were differentially expressed between HCC and paired adjacent normal tissue. Model-constructed genes affected the phosphorylation of mTOR and AKT in both Huh7 and Hep3B cells. Knockdown of ZCRB1 impaired the proliferation, invasion, migration, and colony formation in HCC cell lines.Conclusion: We obtained a prognostic scoring system to forecast the TME changes and assist in choosing therapy strategies for HCC patients. In this study, we combined copper homeostasis and cuproptosis to show the overall potential risk of copper-related biological processes in HCC for the first time.

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Section: Discussionmentioning

confidence: 96%

A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response

Yang

Wang

et al. 2023

Front. Pharmacol.

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“…Interestingly, OBSCN , a new oncogene, significantly mutated in C2. Various studies had shown that the mutation of OBSCN is strongly associated with cancers ( 45 – 47 ). This is consistent with the result that C2 had a poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma

et al. 2022

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Copper (Cu) is an essential element of organisms, which can affect the survival of cells. However, the role of copper metabolism and cuproptosis on hepatic carcinoma is still unclear. In this study, the TCGA database was used as the test set, and the ICGC database and self-built database were used as the validation set. We screened out a class of copper metabolism and cuproptosis-related genes (CMCRGs) that could influence hepatic carcinoma prognosis by survival analysis and differential comparison. Based on CMCRGs, patients were divided into two subtypes by cluster analysis. The C2 subtype was defined as the high copper related subtype, while the C1 subtype was defied as the low copper related subtype. At the clinical level, compared with the C1 subtype, the C2 subtype had higher grade pathological features, risk scores, and worse survival. In addition, the immune response and metabolic status also differed between C1 and C2. Specifically, C2 subtype had a higher proportion of immune cell composition and highly expressed immune checkpoint genes. C2 subtype had a higher TIDE score with a higher proportion of tumor immune dysfunction and exclusion. At the molecular level, the C2 subtype had a higher frequency of driver gene mutations (TP53 and OBSCN). Mechanistically, the single nucleotide polymorphisms of C2 subtype had a very strong transcriptional strand bias for C>A mutations. Copy number variations in the C2 subtype were characterized by LOXL3 CNV gain, which also showed high association with PDCD1/CTLA4. Finally, drug sensitivity responsiveness was assessed in both subtypes. C2 subtype had lower IC50 values for targeted and chemotherapeutic agents (sorafenib, imatinib and methotrexate, etc.). Thus, CMCRGs related subtypes showed poor response to immunotherapy and better responsiveness to targeted agents, and the results might provide a reference for precision treatment of hepatic carcinoma.

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“…TTN, SYNE1, and MUC16 mutations are associated with increased TMB and correlated with an enhanced response to ICB immunotherapy in solid tumors ( 50 – 53 ). OBSCN mutation might promote tumor proliferation, migration, and metastasis ( 54 , 55 ). FAT4 mutation could predict survival outcomes for stratifying patients with colorectal cancer independent of TNM staging ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

Amino acid metabolism-based molecular classification of colon adenocarcinomavia in silico analysis

2022

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Amino acid metabolism is closely related to the occurrence and development of colon adenocarcinoma (COAD). Studies on the relationship between COAD and the expression of amino acid metabolism are still rare. Based on in silico analysis, we used 358 amino acid metabolism-related genes (AAMRGs) to determine the amino acid metabolism characteristics and then classified COAD into two distinct subtypes, namely AA1 and AA2. Then we analyzed the clinical characteristics, somatic mutation landscape, transcriptome profile, metabolism signatures, immune infiltration, and therapy sensitivity of these two subtypes. The AA1 subtype had inferior overall survival and was characterized by lower amino acid metabolic activity, higher tumor mutation burden, and higher immune cell infiltration, while AA2 displayed higher metabolic activity and relatively better survival. Furthermore, the AA1 subtype was likely to benefit from irinotecan in chemotherapy and immune checkpoint blockade therapy including programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) immune checkpoint inhibitor but was resistant to targeted therapy cetuximab. The AA2 subtype showed higher sensitivity to 5-fluorouracil and oxaliplatin. To provide perspectives on cell-specific metabolism for further investigation, we explored metabolic activity in different cell types including lymphocytes, mast cells, myeloid cells stromal cells, and epithelial cells via colorectal cancer single-cell data. Additionally, to assist in clinical decision-making and prognosis prediction, a 60-AAMRG-based classifier was generated and validated in an independent cohort.

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Obscurin: A multitasking giant in the fight against cancer

Cited by 11 publications

References 95 publications

A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response

A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma

Amino acid metabolism-based molecular classification of colon adenocarcinomavia in silico analysis

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