Immunohistochemical profiling of receptor tyrosine kinases, MED12, and TGF-βRII of surgically resected small cell lung cancer, and the potential of c-kit as a prognostic marker

Yokouchi, Hiroshi; Nishihara, Hiroshi; Harada, Toshiyuki; Ishida, Takashi; Yamazaki, Shigeo; Kikuchi, Hajime; Oizumi, Satoshi; Uramoto, Hidetaka; Tanaka, Fumihiro; Harada, Masao; Akie, Kenji; Sugaya, Fumiko; Fujita, Yuka; Takamura, Kei; Kojima, Takao; Higuchi, Mitsunori; Honjo, Osamu; Minami, Yoshinori; Watanabe, Naomi; Goto, Aya; Suzuki, Hiroyuki; Dosaka‐Akita, Hirotoshi; Isobe, Hiroshi; Nishimura, Masaharu; Munakata, Mitsuru

doi:10.18632/oncotarget.14410

Cited by 14 publications

(12 citation statements)

References 43 publications

(44 reference statements)

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“…Thus, the functional link of MED12 and TGF-βR2 only exists in the NSCLC subtype of lung cancer, and MED12 and TGF-βR2 should not be considered as universal biomarkers for all types of lung cancer. 43 We have demonstrated that higher levels of MED12 and CARM1 predict a better response to chemotherapeutics in patients with breast cancer. 31 Methylation of MED12 by CARM1 renders cells sensitive to 5-fluorouracil, but not to the receptor tyrosine kinase inhibitors, in vitro and in vivo, suggesting that the mechanism of mediating drug response in breast cancer cells is different from TGF-βR2-mediated pathways in NSCLC.…”

Section: Med12 In Drug Resistancementioning

confidence: 87%

“…In contrast to NSCLC, MED12 function seems to be intact in small‐cell lung cancer (SCLC), in which no association has been found between the expression of MED12 and TGF‐βR2 or with clinical variables such as overall survival. Thus, the functional link of MED12 and TGF‐βR2 only exists in the NSCLC subtype of lung cancer, and MED12 and TGF‐βR2 should not be considered as universal biomarkers for all types of lung cancer …”

Section: Med12 In Drug Resistancementioning

confidence: 95%

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The emerging role of mediator complex subunit 12 in tumorigenesis and response to chemotherapeutics

Zhang

O’Regan

2019

Cancer

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Transcriptional dysregulation induced by disease‐defining genetic alterations of proteins in transcriptional machinery is a key feature of cancers. Mediator complex subunit 12 (MED12) is the central architectural subunit in the kinase module of Mediator, a large transcriptional regulatory complex that controls essential steps of transcription. Emerging evidence links deregulated MED12 to human cancers. MED12 is frequently mutated in benign tumors and cancers. Although the missense mutations of MED12 in benign tumors disrupt the kinase activity of Mediator, MED12 mutations in cancers could eliminate the interaction between Mediator complex and RNA polymerase II, leading to severe transcriptional misregulation. Aberrant expression of MED12 is associated with the prognosis of various types of human cancers. Loss of MED12 function has been associated with the development of resistance to chemotherapeutics. Moreover, MED12 is modified by posttranscriptional regulations. Arginine methylation of MED12 has been shown to regulate MED12‐mediated transcriptional regulation and response to chemotherapeutics in human cancer cell lines. In this mini‐review, the authors provide an overview of the roles of MED12 in the development of benign and malignant tumors as well as its roles in chemoresistance. The studies of MED12 exemplify that aberrant transcriptional programming is a therapeutic vulnerability for certain types of cancer.

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Section: Med12 In Drug Resistancementioning

confidence: 87%

Section: Med12 In Drug Resistancementioning

confidence: 95%

The emerging role of mediator complex subunit 12 in tumorigenesis and response to chemotherapeutics

Zhang

O’Regan

2019

Cancer

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“…We included patients with primary SCLC who had undergone complete surgical resection of a primary lung tumor between January 2003 and January 2013 at institutions participating in either the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) or the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) . Patients were centrally re‐reviewed for a confirmed pathological diagnosis of pure SCLC or combined SCLC, according to the 2004 World Health Organization classification .…”

Section: Methodsmentioning

confidence: 99%

Analysis of DLL3 and ASCL1 in Surgically Resected Small Cell Lung Cancer (HOT1702)

et al. 2019

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Background Delta‐like protein 3 (DLL3) is a Notch ligand that has an important role in the tumorigenesis of small cell lung cancer (SCLC). Recently, rovalpituzumab tesirine (Rova‐T), a DLL3‐targeted antibody‐drug conjugate, has been developed for treating SCLC. DLL3 is a transcriptional target of the achaete‐scute homolog‐1 (ASCL1) transcription factor, which is involved in pulmonary neuroendocrine cell development. However, the relationship between DLL3 and/or ASCL1 expression and the clinical features of SCLC remains unknown, especially for early‐stage resected SCLC. This study aimed to investigate the expression of DLL3 and ASCL1 in resected SCLC samples using immunohistochemical analysis. Materials and Methods We collected 95 surgically resected SCLC samples, which were formalin fixed and paraffin embedded. Immunohistochemistry staining was performed to investigate the correlation between the expression of either DLL3 or ASCL1 and clinicopathological features of study patients. Results Seventy‐seven (83%) of 93 immunohistochemically evaluable samples were positive for DLL3 (expression in ≥1% of tumor cells), and DLL3‐high expression (≥75%) was observed in 44 samples (47%). Sixty‐one (64%) of 95 samples were positive for ASCL1 (expression in ≥5% of tumor cells). A positive correlation was observed between DLL3 and ASCL1 expression. DLL3 and ASCL1 expression were not associated with survival in SCLC patients. DLL3 was more prevalent in patients with advanced clinical disease. Conclusion DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of SCLC. Implications for Practice This article examines the relationship between delta‐like protein 3 (DLL3) and achaete‐scute homolog‐1 (ASCL1) protein expression with the clinical features of 95 surgically resected small cell lung cancer (SCLC). DLL3 is attracting attention because rovalpituzumab tesirine (Rova‐T), a DLL3‐targeted antibody‐drug conjugate, was developed recently. DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of early‐stage SCLC, including with Rova‐T.

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“…GUCA2A was down-regulated in Subtype-2 samples, many studies on GUCA2A indicates its role as a biomarker in diagnosing cancer. Aberrantly expressed GUCA2A can be a candidate Lou, Jianzhong Wu, 2019) Under expression of TGFBR2 in Subtype-1 samples is associated with poor prognosis, and TGFBR2 is also associated with poor prognosis in cervical cancer (Yang et al, 2017;Yokouchi et al, 2017). CENP-F, a cell cycle-regulated centromere protein, has been shown to affect numerous tumorigenic processes, increased expression of CENP-F in subtype-1 correlates with poor survival.…”

Section: Discussionmentioning

confidence: 99%

Gene prediction in heterogeneous cancer tissues and establishment of Least Absolute Shrinking and Selection Operator model of lung squamous cell carcinoma

Khaliq

Meenakshi

2019

Preprint

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Background. This study is aimed to establish a Least Absolute Shrinking and Selection Operator (LASSO) model based on tumor heterogeneity to predict the best features of LUSC in various cancer subtypes.Methods. The RNASeq data of 505 LUSC cancer samples were downloaded from the TCGA database. Subsequent to the identification of differentially expressed genes (DEGs), the samples were divided into two subtypes based on the consensus clustering method. The subtypes were estimated with the abundance of immune and non-immune stromal cell populations which infiltrated tissue. LASSO model was established to predict each subtype's best genes.Enrichment pathway analysis was then carried out. Finally, the validity of the LUSC model for identifying features was established by the survival analysis.Results. 240 and 262 samples were clustered in Subtype-1 and Subtype-2 groups respectively. DEG analysis was performed on each subtype. A standard cutoff was applied and in total, 4586 genes were upregulated and 1495 were downregulated in case of subtype-1 and 5016 genes were upregulated and 3224 were downregulated in case of subtype-2. LASSO model was established to predict the best features from each subtypes, 49 and 34 most relevant genes were selected in subtype-1 and subtype-2. The abundance of tissue-infiltrates analysis distinguished the subtypes based on the expression pattern of immune infiltrates. Survival analysis showed that this model could effectively predict the best and distinct features in cancer subtypes.Discussion. This study suggests that the unsupervised clustering and LASSO model-based feature selection can be effectively used to predict relevant genes which might play an important role in cancer diagnosis.Bartfay E, Mackillop WJ, Pater JL. 2006. Comparing the predictive value of neural network models to logistic regression models on the risk of death for small-cell lung cancer patients.

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Immunohistochemical profiling of receptor tyrosine kinases, MED12, and TGF-βRII of surgically resected small cell lung cancer, and the potential of c-kit as a prognostic marker

Cited by 14 publications

References 43 publications

The emerging role of mediator complex subunit 12 in tumorigenesis and response to chemotherapeutics

The emerging role of mediator complex subunit 12 in tumorigenesis and response to chemotherapeutics

Analysis of DLL3 and ASCL1 in Surgically Resected Small Cell Lung Cancer (HOT1702)

Gene prediction in heterogeneous cancer tissues and establishment of Least Absolute Shrinking and Selection Operator model of lung squamous cell carcinoma

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