Increased phosphorylation of ERK1/2 is associated with worse chemotherapeutic outcome and a poor prognosis in advanced lung adenocarcinoma

KRAS gene mutation causes lung adenocarcinoma. KRAS activation has been associated with altered glucose and glutamine metabolism. Here, we show that KRAS activates lipogenesis, and this activation results in distinct proteomic and lipid signatures. By gene expression analysis, KRAS is shown to be associated with a lipogenesis gene signature and specific induction of fatty acid synthase (FASN). Through desorption electrospray ionization MS imaging (DESI-MSI), specific changes in lipogenesis and specific lipids are identified. By the nanoimmunoassay (NIA), KRAS is found to activate the protein ERK2, whereas ERK1 activation is found in non-KRAS-associated human lung tumors. The inhibition of FASN by cerulenin, a small molecule antibiotic, blocked cellular proliferation of KRAS-associated lung cancer cells. Hence, KRAS is associated with activation of ERK2, induction of FASN, and promotion of lipogenesis. FASN may be a unique target for KRAS-associated lung adenocarcinoma remediation.

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“…Signatures. KRAS activates ERK signaling (1,3,29). KRASpositive vs. -negative lung tumors were found to exhibit ERK2 vs. ERK1 activation ( Fig.…”

Section: Kras-positive Vs -Negative Tumors Exhibited Unique Erk Proteinmentioning

confidence: 93%

Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma

Gouw

Eberlin

Margulis

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

121

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“…Conversely, a study in patients with non-small cell lung cancer observed that higher levels of cytoplasmic p-AKT had a trend toward longer overall survival; whereas higher levels of nuclear p-AKT had a poorer prognosis [93]. In general, investigators have identified an association between ERK activation and poor prognosis such as aggressive neoplastic features, metastasis, and reduced survival [94,95]. In a study among breast carcinoma patients, p-ERK was shown to be associated with higher TNM stage and lymph node metastasis [96].…”

Section: Leptin Biology and Molecules Of Relevant Signal Transductmentioning

confidence: 99%

The potential role of leptin in tumor invasion and metastasis

Ray

Cleary

2017

Cytokine & Growth Factor Reviews

114

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The adipocyte-released hormone-like cytokine/adipokine leptin behaves differently in obesity compared to its functions in the normal healthy state. In obese individuals, elevated leptin levels act as a pro-inflammatory adipokine and are associated with certain types of cancers. Further, a growing body of evidence suggests that higher circulating leptin concentrations and/or elevated expression of leptin receptors (Ob-R) in tumors may be poor prognostic factors. Although the underlying pathological mechanisms of leptin’s association with poor prognosis are not clear, leptin can impact the tumor microenvironment in several ways. For example, leptin is associated with a number of biological components that could lead to tumor cell invasion and distant metastasis. This includes interactions with carcinoma-associated fibroblasts, tumor promoting effects of infiltrating macrophages, activation of matrix metalloproteinases, transforming growth factor-β signaling, etc. Recent studies also have shown that leptin plays a role in the epithelial-mesenchymal transition, an important phenomenon for cancer cell migration and/or metastasis. Furthermore, leptin’s potentiating effects on insulin-like growth factor-I, epidermal growth factor receptor and HER2/neu have been reported. Regarding unfavorable prognosis, leptin has been shown to influence both adenocarcinomas and squamous cell carcinomas. Features of poor prognosis such as tumor invasion, lymph node involvement and distant metastasis have been recorded in several cancer types with higher levels of leptin and/or Ob-R. This review will describe the current scenario in a precise manner. In general, obesity indicates poor prognosis in cancer patients.

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“…Researchers have been identifying prognostic biomarkers in tumor patients. Proteins such as vascular endothelial growth factor A (VEGF-A) [6], extracellular signal-regulated kinase (ERK) [7], matrix metalloproteinases (MMPs) [8], and pro-apoptotic protein p53 [9] were found to be associated with the overall survival time of patients and the malignant behaviors of some tumors. However, it is still necessary to explore established markers possessing predicative values for the survival of cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Tat-Interacting Protein 30 (TIP30) Expression Serves as a New Biomarker for Tumor Prognosis: A Systematic Review and Meta-Analysis

Jin

Yuan

et al. 2016

PLoS ONE

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BackgroundTat-interacting protein 30 (TIP30) is a tumor suppressor protein that has been found to be expressed in a wide variety of tumor tissues. TIP30 is involved in the control of cell apoptosis, growth, metastasis, angiogenesis, DNA repair, and tumor cell metabolism. The methylation of the TIP30 promoter is also associated with tumor prognosis. To evaluate this topic further, we conducted a systematic meta-analysis to explore the clinicopathological and prognostic significance of TIP30 for tumor patients.MethodsWe searched PubMed and EMBASE for eligible studies. We manually searched for printed journals and relevant textbooks. Subgroup analyses were performed based on the region, manuscript quality, methods of vasculogenic mimicry identification, pathology, and number of patients.ResultsFourteen studies with 1705 patients were included in this meta-analysis. A significant association was observed between high expression of TIP30 in patients with cancer with a good overall survival (hazard ratio = 0.53, 95% confidence interval: 0.41–0.69), and good recurrence-free survival or disease free survival (hazard ratio = 0.49, 95% confidence interval: 0.37–0.66). Lack of expression of TIP30 had an association with lymph node metastasis (odds ratio = 3.90, 95% confidence interval: 2.21–6.89) and high tumor node metastasis clinical stage (odds ratio = 2.10, 95% confidence interval: 1.68–2.62). The methylation of the TIP30 promoter did not significantly influence the overall survival (hazard ratio = 0.99, 95% confidence interval: 0.88–1.13) or disease free survival (hazard ratio = 0.62, 95% confidence interval: 0.19–2.02).ConclusionsTIP30 expression is associated with a good prognosis in patients with tumors. Clinical studies with large samples are needed worldwide and standardized protocols should be adopted in the future to achieve a better understanding of the relationship between tumor prognosis and TIP30.

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Increased phosphorylation of ERK1/2 is associated with worse chemotherapeutic outcome and a poor prognosis in advanced lung adenocarcinoma

Cited by 8 publications

References 47 publications

Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma

Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma

The potential role of leptin in tumor invasion and metastasis

Tat-Interacting Protein 30 (TIP30) Expression Serves as a New Biomarker for Tumor Prognosis: A Systematic Review and Meta-Analysis

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