Lung Adenocarcinoma Tumor Origin: A Guide for Personalized Medicine

Seguin, Laetitia; Durandy, Manon; Feral, Chloé C.

doi:10.3390/cancers14071759

Cited by 77 publications

(59 citation statements)

References 100 publications

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“…Although there are several therapeutic options for lung cancer, including surgery, chemotherapy, radiotherapy and targeted therapy, the overall prognosis is still far from satisfactory, with a 5-year survival rate about 19% [ 3 – 5 ]. The difficulty in treating LUAD is mostly due to the high heterogeneity of LUAD [ 6 ]. Therefore, exploring more efficient biomarkers is crucial for diagnosis, prognosis, and risk assessment of LUAD.…”

Section: Introductionmentioning

confidence: 99%

Decreased INPP5B expression predicts poor prognosis in lung adenocarcinoma

Deng

Lin

et al. 2022

Cancer Cell Int

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Background Inositol Polyphosphate-5-Phosphatase B (INPP5B), a inositol 5-phosphatase, plays an important role in many biological processes through phosphorylating PI(4,5)P2 and/or PI(3,4,5)P3 at the 5-position. Nevertheless, little is known about its function and cellular pathways in tumors. This study aims to investigate the potential role of INPP5B as a diagnostic and prognostic biomarker for lung adenocarcinoma (LUAD), as well as its biological functions and molecular mechanisms in LUAD. Methods TCGA, GEO, CTPAC, and HPA datasets were used for differential expression analysis and pathological stratification comparison. The prognostic and diagnostic role of INPP5B was determined by Kaplan–Meier curves, univariate and multivariate Cox regression analysis, and receiver operating characteristics (ROC) curve analyses. The potential mechanism of INPP5B was explored through GO, KEGG, and GSEA enrichment analysis, as well as GeneMANIA and STRING protein–protein interaction (PPI) network. PicTar, PITA, and miRmap databases were used for exploring miRNA targeting INPP5B. In molecular biology experiments, immunohistochemical analyses and Western blot analyses were used to determine protein expression. Co-immunoprecipitation assay was used to detect protein–protein interactions. CCK8 assays and colony formation assays were used for the measurement of cell proliferation. Cell cycle was assessed by PI staining with flow cytometry. Cell migration was performed by Transwell assays and wound healing assays. Result INPP5B was decreased in LUAD tissues compared with normal adjacent tissues. And the low expression of INPP5B was associated with late-stage pathological features. In addition, INPP5B was found to be a significant independent prognostic and diagnostic factor for LUAD patients. Hsa-miR-582-5p was predicted as a negative regulator of INPP5B mRNA expression. INPP5B was significantly correlated with the expression of PTEN and the activity of PI3K/AKT signaling pathways, as determined by enrichment analysis and PPI network. In vitro experiments partially confirmed the aforementioned findings. INPP5B could interact directly with PTEN. INPP5B overexpression inhibited LUAD cell proliferation and migration while downregulating the AKT pathway. Conclusion Our results demonstrated that INPP5B could inhibit the proliferation and metastasis of LUAD cells. It could serve as a novel diagnostic and prognostic biomarker for LUAD patients. Trial registration LUAD tissues and corresponding para-cancerous tissues were collected from 10 different LUAD patients at Hangzhou First People’s Hospital. The Ethics Committee of Hangzhou First People’s Hospital has approved this study. (registration number: IIT-20210907-0031-01; registration date: 2021.09.13)

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Section: Introductionmentioning

confidence: 99%

Decreased INPP5B expression predicts poor prognosis in lung adenocarcinoma

Deng

Lin

et al. 2022

Cancer Cell Int

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“…In addition, the high incidence of resistance to radiotherapy and immunotherapy has contributed to unfavorable clinical outcomes for patients. Lung cancer is a highly heterogeneous tumor, and its occurrence is the result of coregulation of multiple genes [ 5 ]. In-depth investigation of the molecular mechanism of LUAD will provide valuable guidance for early diagnosis and individualized treatment of LUAD.…”

Section: Introductionmentioning

confidence: 99%

A Connexin-Based Biomarker Model Applicable for Prognosis and Immune Landscape Assessment in Lung Adenocarcinoma

Yin

Ding

2022

Journal of Oncology

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Purpose. Gap junction protein (Connexin) family is the basic unit of cellular connection, whose multiple members were recently demonstrated to be associated with tumor progression. However, the expression pattern and prognostic value of connexin in lung adenocarcinoma (LUAD) have not yet been elucidated. Methods. Consensus cluster algorithm was first applied to determine a novel molecular subtype in LUAD based on connexin genes. The differentially expressed genes (DEGs) between two clusters were obtained to include in Cox regression analyses for the model construction. To examine the predictive capacity of the signature, survival curves and ROC plots were conducted. We implemented GSEA method to uncover the function effects enriched in the risk model. Moreover, the tumor immune microenvironment in LUAD was depicted by CIBERSORT and ssGSEA methods. Results. The integrated LUAD cohort (TCGA-LUAD and GSE68465) were clustered into two subtypes ( C 1 = 217 and C 2 = 296 ) based on 21 connexins and the clinical outcomes of LUAD cases in the two clusters showed remarkable discrepancy. Next, we collected 222 DEGs among two subclusters to build a prognostic model using stepwise Cox analyses. Our proposed model consisted of six genes that accurately forecast patient outcomes and differentiate patient risk. GSEA indicated that high-risk group was involved in tumor relevant pathways were activated in high-risk group, such as PI3K/AKT signaling, TGF-β pathway, and p53 pathway. Furthermore, LUAD cases with high-risk presented higher infiltration level of M2 macrophage and neutrophil, suggesting high-risk group were more likely to generate an immunosuppressive status. Conclusion. Our data identified a novel connexin-based subcluster in LUAD and further created a risk signature which plays a central part in prognosis assessment and clinical potency.

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“…The initial symptoms of LUAD are often not obvious, and by the time the disease becomes apparent, it is already in an advanced stage. LUAD is treated with radiotherapy, chemotherapy, immune checkpoint inhibitor therapy, and molecular targeted therapy, of which molecular targeted therapy has achieved excellent results in recent years but is prone to treatment resistance ( Drosten and Barbacid, 2022 ; Seguin et al, 2022 ). Lung cancer is often accompanied by abnormal expression of multiple genes, and recent studies have indicated that multigene-targeted treatments have favorable therapeutic effects ( Piñeiro-Yáñez et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of histone methylation modification regulators for predicting prognosis and drug sensitivity in lung adenocarcinoma

Dai

et al. 2022

Front. Cell Dev. Biol.

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Histone methylation is an epigenetic modification regulated by histone methyltransferases, histone demethylases, and histone methylation reader proteins that play important roles in the pathogenic mechanism of cancers. However, the prognostic value of histone methylation in lung adenocarcinoma (LUAD) remains unknown. Here, we found that LUAD cases could be divided into 2 subtypes by the 144 histone methylation modification regulators (HMMRs), with a significant difference in OS time. Ninety-five of the HMMRs were identified as differentially expressed genes (DEGs) between normal and tumor samples, and 13 of them were further discovered to be survival-related genes (SRGs). By applying the least absolute shrinkage and selector operator (LASSO) Cox regression, we constructed an 8-gene-based risk signature according to the TCGA (training) cohort, and the risk score calculated by the signature was proven to be an independent factor in both the training and validation cohorts. We then discovered that the immune functions were generally impaired in the high-risk groups defined by the HMMR signature (especially for the DCs and immune check-point pathway). Functional analyses showed that the DEGs between the low- and high-risk groups were related to the cell cycle. The drug sensitivity analysis indicated that our risk model could predict the sensitivity of commonly used drugs. Moreover, according to the DEGs between the low- and high-risk groups, we discovered several new compounds that showed potential therapeutic value for high-risk LUAD patients. In conclusion, our study demonstrated that HMMRs were promising predictors for the prognoses and drug therapeutic effects for LUAD patients.

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Lung Adenocarcinoma Tumor Origin: A Guide for Personalized Medicine

Cited by 77 publications

References 100 publications

Decreased INPP5B expression predicts poor prognosis in lung adenocarcinoma

Decreased INPP5B expression predicts poor prognosis in lung adenocarcinoma

A Connexin-Based Biomarker Model Applicable for Prognosis and Immune Landscape Assessment in Lung Adenocarcinoma

Comprehensive analysis of histone methylation modification regulators for predicting prognosis and drug sensitivity in lung adenocarcinoma

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