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Proteome profiling of formalin-fixed, paraffin-embedded lung adenocarcinoma tissues using a tandem mass tag-based quantitative proteomics approach.

ABSTRACT: Over the past few decades, increasing efforts have been made to improve the understanding of, and treatment options for, lung adenocarcinoma (LUAD). However, considering the heterogeneity of LUAD, precise proteomics-based characterization at the molecular level is an urgent clinical requirement for effective treatment. Formalin-fixed, paraffin-embedded (FFPE) tissue is a good option as the working tool for proteomics studies. The present study aimed to obtain a global protein profile using LUAD FFPE tissue samples. Using a quantitative proteomics approach, the study revealed that 360 proteins were significantly more highly expressed in LUAD than in adjacent nontumor lung tissues. Also, 19 differentially expressed membrane proteins were found to be primarily responsible for immune processes. Epidermal growth factor (EGF)-like domain and laminin EGF domain showed markedly different expression levels between cancer tissues and tumor-adjacent normal tissues. Furthermore, Gene Ontology functional enrichment analysis showed that significantly upregulated proteins were associated with the endoplasmic reticulum lumen, protein disulfide isomerase activity, vitamin binding, cell cycle G₁/S phase transition, to name but a few. Also, numerous kinases and post-translational modification enzymes were significantly upregulated across all eight LUAD samples compared with paracarcinoma tissues. Proteomics analysis revealed that AAA domain containing 3A (ATAD3a), a member of the ATPase family, was highly expressed in LUAD tissues, which was supported by immunohistochemical analysis. Furthermore, the study confirmed that ATAD3a enhanced the cisplatin sensitivity of LUAD cells. Collectively, the findings of the present study provide new potential candidate targets in patients with LUAD, and may aid auxiliary LUAD diagnosis and surveillance in a noninvasive manner.

SUBMITTER: Xie Q

PROVIDER: S-EPMC8358594 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:There is increasing acceptance of the critical importance of correlating the morphologic features of tissue with the data obtained from various molecular analytic techniques. Access to archived formalin-fixed and paraffin-embedded (FFPE) tissue specimens via shotgun-based proteomic analyses may, therefore, open new avenues for both prospective and retrospective translational research. However, one of the remaining issues in performing comparative proteomic measurements among FFPE tissues relates to potential variability in protein composition and retrieval based on length of storage periods. Optimized protein extraction and digestion procedures for handling FFPE tissues are coupled with the capillary isotachophoresis-based proteome technology to evaluate the effects of length of storage period on archival tissue proteome analysis across 10 archived uterine mesenchymal tumor tissue blocks, including 9 uterine leiomyomas dating from 1990 to 2002 and a single case of alveolar soft part sarcoma (ASPS) from 1980. Several statistical measures, including the Pearson correlation coefficient, coefficient of variance, k-means clustering, and ANOVA, are employed to evaluate the possibility of an archival effect on individual proteins or groups of proteins within nine leiomyomas. Low abundance proteins may be more susceptible to the long-term storage as these proteins are more difficult to be retrieved and extracted as the tissue block ages in paraffin. Despite using tissue blocks stored for as many as 28 years, high confidence and comparative proteome analysis between the leiomyomas and the sarcoma is achieved. Though sharing over 1800 common proteins in a core set, a total of 80 proteins unique to the sarcoma are identified distinguishing the ASPS from the leiomyomas. Vacuolar proton translocating ATPase 116 kDa subunit isoform a3, one of the unique proteins expressed in the ASPS, is further validated by immunohistochemistry (IHC). Although IHC is highly sensitive and provides the subcellular resolution, mass spectrometry-based proteome profiling enables global identification and quantification of thousands of proteins without a priori knowledge of individual proteins being analyzed or the need of validated antibodies.

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Proteome profiling of formalin-fixed, paraffin-embedded lung adenocarcinoma tissues using a tandem mass tag-based quantitative proteomics approach.

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