Smad4 loss promotes lung cancer formation but increases sensitivity to DNA topoisomerase inhibitors

Haeger, Sarah M.; Thompson, Jeffrey Y.; Kalra, Sean; Cleaver, Timothy G.; Merrick, Daniel T.; Wang, Xiaojing; Malkoski, Stephen P.

doi:10.1038/onc.2015.112

Cited by 36 publications

(48 citation statements)

References 50 publications

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“…The underlying mechanisms include mutation, homozygous deletion, and heterozygous loss. 42 Downregulation of SMAD4 gene expression may lead to lung carcinogenesis. 43 Bian et al 44 found that decreased SMAD4 was important for LUAD occurrence and development and predicted a poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Clinical value of miR-145-5p in NSCLC and potential molecular mechanism exploration: A retrospective study based on GEO, qRT-PCR, and TCGA data

et al. 2017

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MicroRNAs have been reported to be involved in various biological processes. Here, we performed a systematic analysis to explore the clinical value and potential molecular mechanism of miR-145-5p in non-small cell lung cancer. First, a meta-analysis was performed with eligible literature, followed by microRNA microarrays in the Gene Expression Omnibus database, to verify the diagnostic and prognostic values of miR-145-5p. A cohort of 125 clinical paired non-small cell lung cancer samples was next used to detect the level of miR-145-5p and to explore the relationship of miR-145-5p with clinicopathological parameters. The Cancer Genome Atlas database was additionally applied to investigate the role of miR-145-5p in non-small cell lung cancer. The potential targets of miR-145-5p were predicted using 12 online prediction databases to explore the prospective molecular mechanism of miR-145-5p in non-small cell lung cancer. The expression of miR-145-5p in non-small cell lung cancer was significantly lower than that in healthy tissues. And miR-145-5p tended to show better diagnostic performance in lung squamous cell carcinoma than in lung adenocarcinoma. Furthermore, the expression of miR-145-5p was closely associated with lymph node metastasis in non-small cell lung cancer. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the target genes were mainly enriched with enzyme-linked receptor protein signaling pathways, SH3 domain binding, cell leading edge, and adherens junction. The protein-protein interaction network showed that eight hub genes (SMAD4, SMAD2, IRS1, FOXO1, ERBB4, NRAS, ACTB, and ACTG1) might be the key target genes of miR-145-5p in non-small cell lung cancer. The information we obtained might offer new perspectives for clinical diagnosis and treatment for non-small cell lung cancer.

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Section: Discussionmentioning

confidence: 99%

Clinical value of miR-145-5p in NSCLC and potential molecular mechanism exploration: A retrospective study based on GEO, qRT-PCR, and TCGA data

et al. 2017

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“…We previously found that reduced Smad4 expression in vitro increased sensitivity to gemcitabine and etoposide [9]. Therefore we assessed the relationship between Smad4 expression and clinical response to these agents in human NSCLC patients.…”

Section: Resultsmentioning

confidence: 99%

“…Paraffin sections were obtained from the University of Colorado Lung Cancer SPORE tissue bank then immunohistochemistry (IHC) was performed as previously described [9]. After heat-mediated antigen retrieval in 8mM sodium citrate, 0.05% Tween 20, pH 6, sections were incubated overnight at 4°C with anti-Smad4 antibody (1:100; Abcam; ab40759).…”

Section: Methodsmentioning

confidence: 99%

“…In both lung and pancreatic cancer, reduced Smad4 immunostaining has been associated with reduced survivial [10, 11]. The role of Smad4 as a tumor suppressor has been confirmed in animals models where Smad4 loss initiates tumor formation [9, 12], promotes the progression of oncogene-initiated lesions [13, 14], and stimulates the development of metastases [10, 15]. …”

Section: Introductionmentioning

confidence: 99%

“…We previously reported that reduced Smad4 expression in NSCLC is associated with increased DNA damage, reduced DNA repair, and increased sensitivity to topoisomerase inhibitors in vitro [9]. In this study, we retrospectively assessed the relationship between Smad4 expression in human NSCLC and the clinical response to two chemotherapeutic drugs that have activity against DNA topoisomerase.…”

Section: Introductionmentioning

confidence: 99%

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Reduced Smad4 expression and DNA topoisomerase inhibitor chemosensitivity in non-small cell lung cancer

et al. 2017

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Objective Smad4 is a tumor suppressor that transduces transforming growth factor beta signaling and regulates genomic stability. We previously found that Smad4 knockdown in vitro inhibited DNA repair and increased sensitivity to DNA topoisomerase inhibitors. In this study, we assessed the association between reduced Smad4 expression and DNA topoisomerase inhibitor sensitivity in human non-small cell lung cancer (NSCLC) patients and evaluated the relationship between genomic alterations of Smad4 and molecular alterations in DNA repair molecules. Materials and Methods We retrospectively identified NSCLC patients who received etoposide or gemcitabine. Chemotherapeutic response was quantified by RECIST 1.1 criteria and Smad4 expression was assessed by immunohistochemistry. Relationships between Smad4 mutation and DNA repair molecule mutations were evaluated using publically available datasets. Results We identified 28 individuals who received 30 treatments with gemcitabine or etoposide containing regimens for NSCLC. Reduced Smad4 expression was seen in 13/28 patients and was not associated with significant differences in clinical or pathologic parameters. Patients with reduced Smad4 expression had a larger response to DNA topoisomerase inhibitor containing regimens then patients with high Smad4 expression (−25.7% vs. −6.8% in lesion size, p=0.03); this relationship was more pronounced with gemcitabine containing regimens. The overall treatment response was higher in patients with reduced Smad4 expression (8/14 vs 2/16 p=0.02). Analysis of data from The Cancer Genome Atlas revealed that Smad4 mutation or homozygous loss was mutually exclusive with genomic alterations in DNA repair molecules. Conclusions Reduced Smad4 expression may predict responsiveness to regimens that contain DNA topoisomerase inhibitors. That Smad4 signaling alterations are mutually exclusive with alterations in DNA repair machinery is consistent with an important role of Smad4 in regulating DNA repair.

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Inter‐ and intra‐tumor heterogeneity of SMAD4 loss in head and neck squamous cell carcinomas

Hernandez¹,

Wang

Somerset³

et al. 2019

Molecular Carcinogenesis

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Reports regarding the frequency of SMAD4 loss in human head and neck squamous cell carcinoma (HNSCC) vary significantly. We have shown that SMAD4 deletion contributes to HNSCC initiation and progression. Therefore, accurately detecting genetic SMAD4 loss is critical to determine prognosis and therapeutic interventions in personalized medicine. We developed a SMAD4 fluorescence in situ hybridization (FISH) assay to identify chromosomal SMAD4 loss at the single cell level of primary HNSCC specimens and patient derived xenograft (PDX) tumors derived from HNSCCs. SMAD4 heterozygous loss was detected in 35% of primary HNSCCs and 41.3% of PDX tumors. Additionally, 4.3% of PDX tumors had SMAD4 homozygous loss. These frequencies of SMAD4 loss were similar to those in The Cancer Genome Atlas (TCGA). However, we identified significant heterogeneities of SMAD4 loss (partial or complete) among cells within each tumor. We also found that aneuploidy (monosomy and polysomy) contributed greatly to how to define chromosomal SMAD4 deletion. Furthermore, in cultured PDX tumors, SMAD4 mutant cells outcompeted SMAD4 wildtype cells, resulting in establishing homogenous SMAD4 mutant HNSCC cell lines with partial or complete genomic SMAD4 loss, suggesting a survival advantage of SMAD4 mutant cells. Taken together, our study reveals inter- and intra-tumor heterogeneities of SMAD4 chromosomal loss in HNSCCs. Further, SMAD4 FISH assay provides a platform for future clinical diagnosis of SMAD4 chromosomal loss that potentially serves as a molecular marker for prognosis and therapeutic intervention in cancer patients.

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Smad4 loss promotes lung cancer formation but increases sensitivity to DNA topoisomerase inhibitors

Cited by 36 publications

References 50 publications

Clinical value of miR-145-5p in NSCLC and potential molecular mechanism exploration: A retrospective study based on GEO, qRT-PCR, and TCGA data

Clinical value of miR-145-5p in NSCLC and potential molecular mechanism exploration: A retrospective study based on GEO, qRT-PCR, and TCGA data

Reduced Smad4 expression and DNA topoisomerase inhibitor chemosensitivity in non-small cell lung cancer

Inter‐ and intra‐tumor heterogeneity of SMAD4 loss in head and neck squamous cell carcinomas

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