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

Ziemke, Michael; Patil, Tejas; Nolan, Kyle; Tippimanchai, D.; Malkoski, Stephen P.

doi:10.1016/j.lungcan.2017.04.017

Cited by 11 publications

(12 citation statements)

References 35 publications

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“…SMAD-4 binds to other active R-SMAD proteins (SMAD-1/2/3/5/8) to form homo-and heterotypic complexes that accumulate in the nucleus and regulate transcription of target genes, including Nanog, CDKN1C, CDKN2B, Nodal, PAI-1, Lefty1 and SMAD7 (6). SMAD-4 appears to function as a tumor suppressor in lung carcinoma and is associated with the differentiation status of lung carcinoma tissues (61,62). It was found that the p.R361C mutation in SMAD-4 serves a role in downregulating the TGF-β signaling pathway, causing a loss of growth inhibition and transcriptional activation mediated by SMADs, and it is hypothesized that the mutation p.R361C in SMAD-4 plays a crucial part in lung oncogenesis (63).…”

Section: Discussionmentioning

confidence: 99%

SMAD‑6, ‑7 and ‑9 are potential molecular biomarkers for the prognosis in human lung cancer

Pan

Zhou

et al. 2020

Oncol Lett

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SMADs, a family of proteins that function as signal transducers and transcriptional regulators to regulate various signaling pathways, including the transforming growth factor-β signaling pathway, are similar to the mothers against decapentaplegic family of genes and the sma gene family in Caenorhabditis elegans. SMADs generate context-dependent modulation by interacting with various sequence-specific transcription factors, such as E2F4/5, c-Fos, GATA3, YY1 and SRF, which have been found to serve a key role in lung carcinoma oncogenesis and progression. However, the prognostic values of the eight SMADs in lung cancer have not been fully understood. In the present study, the expression levels and survival data of SMADs in patients with lung carcinoma from the Oncomine, Gene Expression Profiling Interactive Analysis, Kaplan-Meier plotter and cBioPortal databases were downloaded and analyzed. It was found that the mRNA expression levels of SMAD-6,-7 and-9 were decreased in lung adenocarcinoma and squamous cell carcinoma compared with that in adjacent normal tissues, while there was no significant difference in SMADs 1-5. Survival analysis revealed that not only were low transcriptional levels of SMAD-6,-7 and-9 associated with low overall survival but they also had prognostic role for progression-free survival and post-progression survival (P<0.05) in patients with lung carcinoma. In conclusion, the present study demonstrated that SMAD-6,-7 and-9 are potential biomarkers for the prognosis of patients with lung carcinoma.

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Section: Discussionmentioning

confidence: 99%

SMAD‑6, ‑7 and ‑9 are potential molecular biomarkers for the prognosis in human lung cancer

Pan

Zhou

et al. 2020

Oncol Lett

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“…A previous study for cancer genome map research shows that 13% of LSCC and 47% of LAC have Smad4 deletion [ 16 ]. The deletion of Smad4 can promote the formation of lung cancer by inhibiting DNA repair and at the same time make the tumor itself more sensitive to topoisomerase inhibitors, which is related to the regulatory mechanism of DNA repair of Smad4 [ 17 ]. Although we observed that the serum Smad4 concentration of female patients was lower than that of males, we found that it was related to the high rate of LAC in female patients through data analysis.…”

Section: Discussionmentioning

confidence: 99%

Correlation between loss of Smad4 and clinical parameters of non-small cell lung cancer: an observational cohort study

Guo

Wang

et al. 2021

BMC Pulm Med

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Background SMAD4 has been found to be inactivated to varying degrees in many types of cancer; the purpose of this study was to investigate the correlation between SMAD4 expression in non-small cell lung cancer (NSCLC) and clinical pathological parameters. Methods The serum concentration of SMAD4 was measured by enzyme-linked immunosorbent assay and its histological expression was quantified by immunohistochemistry. Results The serum concentration of Smad4 in patients with NSCLC was lower than that in benign lung disease patients and healthy individuals (P < 0.001) and its concentration was related to the histological classification, pathological differentiation, lymphatic metastasis and clinical stage of NSCLC. The sensitivity and specificity of serum Smad4 were 91.56% and 61.56% for screening NSCLC from healthy individuals and 84.55% and 60.36% for screening NSCLC from patients with benign lung disease. Logistic regression analysis showed that the degree of cell differentiation (P < 0.001), lymph node metastasis (P < 0.001) and clinical stage of NSCLC (P = 0.007) affected the expression of Smad4, and had a strong correlation with the expression of Smad4. The expression of Smad4 in NSCLC tissues was lower than that in normal lung tissues (P = 0.009) and its expression was related to the degree of tissue differentiation, lymph node metastasis and clinical stage (P < 0.05). Conclusions The downregulation or deletion of Smad4 is related to the malignant biological behavior of NSCLC and serum Smad4 could be considered as a potential molecular indicator for diagnosis and evaluation of NSCLC.

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“…PCR primer sequences are shown in Table 1 . Presence or absence of target gene products (or downstream targets) was also evaluated by Western blotting as previously described [ 33 ] using the following antibodies: KRAS G12D (Cell Signaling #14429 1:1000), SMAD4 (Abcam #ab40759 1:5000), TGFBR2 (R&D Systems #AF532), TP53 (Cell Signaling #32532 1:1000), PTEN (Cell Signaling #9559 1:1000), MAP3K7 (Cell Signaling #4505 1:1000), pAKT-Ser473 (Cell Signaling #4058 1:1000), total AKT (Cell Signaling #4691 1:1000), GAPDH (Abcam #ab8245 1:10,000). CMT167 and LLC control cells were kindly provided by Dr. Raphael Nemenoff (University of Colorado Anschutz Medical Campus).…”

Section: Methodsmentioning

confidence: 99%

Development of syngeneic murine cell lines for use in immunocompetent orthotopic lung cancer models

et al. 2020

Self Cite

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Background Immunocompetent animal models are required to study tumor-host interactions, immunotherapy, and immunotherapeutic combinations, however the currently available immunocompetent lung cancer models have substantial limitations. While orthotopic models potentially help fill this gap, the utility of these models has been limited by the very small number of murine lung cancer cell lines capable of forming orthotopic tumors in immunocompetent C57BL/6 hosts. Methods Primary lung tumors with specific genetic alterations were created in C57BL/6 background mice. These tumors were then passaged through other animals to increase tumorigenicity and select for the ability to grow in a non-self animal. Once tumors demonstrated growth in a non-self host, cell lines were established. Successful cell lines were evaluated for the ability to produce orthotopic lung tumors in immunocompetent hosts. Results We produced six murine lung cancer lines capable of orthotopic lung tumor formation in immunocompetent C57BL/6 animals. These lines demonstrate the expected genetic alterations based on their primary tumor genetics. Conclusions These novel cell lines will be useful for evaluating tumor-host interactions, the impact of specific oncogenic alterations on the tumor microenvironment, and immunotherapeutic approaches. This method of generating murine lines capable of orthotopic growth can likely be applied to other tumors and will broaden the applicability of pre-clinical testing of immunotherapeutic treatment regimens.

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

Cited by 11 publications

References 35 publications

SMAD‑6, ‑7 and ‑9 are potential molecular biomarkers for the prognosis in human lung cancer

SMAD‑6, ‑7 and ‑9 are potential molecular biomarkers for the prognosis in human lung cancer

Correlation between loss of Smad4 and clinical parameters of non-small cell lung cancer: an observational cohort study

Development of syngeneic murine cell lines for use in immunocompetent orthotopic lung cancer models

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