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Initial Insights on the Proteomic Profile of Filipino Non-Small Cell Lung Carcinoma (NSCLC)

ABSTRACT: NSCLC remains to be the leading cause of cancer incidence and mortality in the Philippines. Early diagnosis, better understanding on the mechanisms of drug resistance, and proper treatment monitoring is necessary to lower the incidence and mortality rate of NSCLC. This study was able to provide initial insights on the proteomic profile of Filipino NSCLC by quantitative proteomic analysis and identification of aberrant expressions in the tumor tissue relative to the adjacent normal tissue specimen. A total of 4518 proteins were identified and from this, 1855 proteins were found to be significantly upregulated and downregulated. Functional and pathway analysis was done to the upregulated and downregulated proteins with at least 4-fold expression change. Pathway analysis revealed the possible activation of the upregulated protein, MUC1, which is a known oncogenic driver involved in the stimulation of pathways that promote angiogenesis in NSCLC tumor, and prevention of apoptosis. STAT1 and STAT3, also found upregulated in the tumor specimen, were known to have interactions with MUC1 which results to expression of proteins for cell proliferation. The analysis also suggests the stabilization of HIF which allows cell growth in the hypoxic tumor environment, and the activation of EIF signaling correlated with low survival rate of NSCLC patients. Our data demonstrate the rich proteomic information that can be obtained from comprehensive profiling of the NSCLC proteome and applications for better understanding of NSCLC tumorigenicity.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung

DISEASE(S): Non-small Cell Lung Carcinoma

SUBMITTER: Baby Rorielyn Dimayacyac-Esleta

LAB HEAD: Dr. Baby Rorielyn T. Dimayacyac-Esleta

PROVIDER: PXD027710 | Pride | 2022-02-10

REPOSITORIES: Pride

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Project description:Introduction: Targeting of the tumor vasculature has evolved into an integral part of existing standard anti-cancer therapies. However, recent pre-clinical and clinical studies have shown that the efficacy of these treatments is temporary at most and frequently followed by the renewed tumor growth, indicating that these targets may not be robust. Methods: We transcriptionally profiled laser capture microdissection isolated microvessels from tumor and matching adjacent normal tissue samples obtained from breast cancer patients diagnosed with infiltrating ductal carcinoma. Gene expression profiles were generated and analyzed using Genespring and the web-based WebGestalt bioinformatics Toolkit. Several differentially expressed genes were validated by immunohistochemistry. To further mine our data set we used a novel integrative systems biology network approach to identify a gene signature that could robustly stratify breast cancer patient populations. Results: Vascular enrichment of the LCM samples was confirmed by Q-PCR of CD31. Hierarchical two-dimensional clustering of the transcriptome data identified 219 significantly upregulated transcripts in at least 4/8 patient samples (cut-off >1.3-fold, p<0.05). Several genes AGRN, FLNA and ILR4 were selected and their protein overexpression was confirmed in the tumor tissue. Additional mining of the data set using the clinical information associated with these tissues by applying an integrative bioinformatics network method generated a 15-gene M-bM-^@M-^XVascular-Derived Prognostic PredictorM-bM-^@M-^Y that is able to stratify patient populations in to high- and low- risk groups. Conclusions: The overall heterogeneity observed in the vascular gene expression patterns in the infiltrating ductal carcinoma samples poses a significant problem for these individual genes to be used as a robust vascular breast cancer specific marker or therapeutic target. Using an integrative bioinformatics network approach allowed us to identify a 15-gene M-bM-^@M-^XVascular-Derived Prognostic PredictorM-bM-^@M-^Y that can robustly identify patients with an increased risk of local recurrence. Stratifying patient populations using this gene signature may lead to better patient-tailored treatment regimes. Two-color microarrays comparing laser-captured microvessels from the tumors and matching adjacent normal tissues of 8 breast cancer patients

Project description:Patients with loss-of-function mutations of the von Hippel Lindau gene (“VHL-patients”) often develop clear cell renal cell carcinoma (ccRCC). Using archived, formalin-fixed, paraffin-embedded (FFPE) samples and a cohort of eight cases, we sought to determine global proteome alterations that distinguish ccRCC tissue from adjacent, non-malignant kidney tissue in VHL-patients. Our quantitative proteomic analysis clearly discriminated tumor and non-malignant tissue, yielding comparable proteome profiles for the eight ccRCC cases. Limma statistics was used to identify significantly dysregulated proteins in ccRCC. Functional classification of these proteins highlighted a decrease in proteins involved in the tricarboxylic acid cycle and an increase in proteins involved in glycolysis. This profile possibly represents a proteomic fingerprint of the “Warburg effect”, which is a molecular hallmark of ccRCC. Furthermore, we observed an increase in proteins involved in extracellular matrix organization. Of particular note were opposing alterations of Xaa-Pro Aminopeptidases-1 and -2 (XPNPEP-1 and -2): a strong decrease of XPNPEP-2 in ccRCC was accompanied by a strong increase of the related protease XPNPEP-1. In both cases, we corroborated the proteomic results by immunohistochemical analysis of ccRCC and adjacent, non-malignant kidney tissue of VHL patients. To functionally investigate the role of XPNPEP-1 in ccRCC, we performed small-hairpin RNA mediated XPNPEP-1 expression silencing in 786-O ccRCC cells harboring a mutated VHL gene. We found that XPNPEP-1 expression suppresses cellular proliferation and migration. These results suggest that XPNPEP-1 is rather an anti-target in VHL-driven ccRCC. Generally, we present one of the first proteomic profiling studies of ccRCC in VHL patients, comparing normal and tumor tissue, which are both deficient for the VHL tumor suppressor. Methodologically, our work further validates the robustness of using FFPE material for quantitative proteomics.

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Initial Insights on the Proteomic Profile of Filipino Non-Small Cell Lung Carcinoma (NSCLC)

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