Comprehensive analysis of tissue proteomics in patients with papillary thyroid microcarcinoma uncovers the underlying mechanism of lymph node metastasis and its significant sex disparities

Abstract

BackgroundLymph node metastasis (LNM) in papillary thyroid microcarcinoma (PTMC) is associated with an increased risk of recurrence and poor prognosis. Sex has been regarded as a critical risk factor for LNM. The present study aimed to investigate the molecular mechanisms underlying LNM and its significant sex disparities in PTMC development.MethodsA direct data-independent acquisition (DIA) proteomics approach was used to identify differentially expressed proteins (DEPs) in PTMC tumorous tissues with or without LNM and from male and female patients with LNM. The functional annotation of DEPs was performed using bioinformatics methods. Furthermore, The Cancer Genome Atlas Thyroid Carcinoma (TCGA-THCA) dataset and immunohistochemistry (IHC) were used to validate selected DEPs.ResultsThe proteomics profile in PTMC with LNM differed from that of PTMC without LNM. The metastasis-related DEPs were primarily enriched in categories associated with mitochondrial dysfunction and may promote tumor progression by activating oxidative phosphorylation and PI3K/AKT signaling pathways. Comparative analyses of these DEPs revealed downregulated expression of specific proteins with well-established links to tumor metastasis, such as SLC25A15, DIRAS2, PLA2R1, and MTARC1. Additionally, the proteomics profiles of male and female PTMC patients with LNM were dramatically distinguishable. An elevated level of ECM-associated proteins might be related to more LNM in male PTMC than in female PTMC patients. The upregulated expression levels of MMRN2 and NID2 correlated with sex disparities and showed a positive relationship with unfavorable variables, such as LNMs and poor prognosis.ConclusionsThe proteomics profiles of PTMC show significant differences associated with LNM and its sex disparities, which further expands our understanding of the functional networks and signaling pathways related to PTMC with LNM.

In search of new stratification strategies: tissue proteomic profiling of papillary thyroid microcarcinoma in patients with localized disease and lateral neck metastases

“…In a tissue-based proteomic study, Cao et al compared papillary microcarcinoma tissues depending on metastases, although not specifying whether they were central or lateral, and found signi cant differences in differentially expressed proteins (DEP), namely downregulation of Solute Carrier Family 25 Member 15, DIRAS Family GTPase 2, Phospholipase A2 receptor 1 and Mitochondrial Amidoxime Reducing Component 1, while these DEPs were enriched in mitochondrial dysfunction, possibly promoting tumorigenesis by activating the PI3K/AKT signalling pathways. Interestingly, this research has also found signi cant differences in proteomic pro les depending on sex (71).…”

Papillary thyroid carcinoma: ≤ 10 mm does not always mean pN0. A multicentric real-world study

“…Therefore, strong input emerging from this study concerns the need for efforts in the development of proteomic assays in thyroid cytological samples, rather than genomics, to detect mutated proteins that could promote metastasis. Proteins that characterize mitochondrial inner membrane, mitochondrial transport, cell respiration, and ribosomal activity have already been reported to be more expressed in tissues of PTMC with LNM than those without LNM [ 28 ]. Hence, it was hypothesized that mitochondrial dysfunction may promote tumor progression by activating oxidative phosphorylation and PI3K/AKT signaling pathways.…”

“…Hence, it was hypothesized that mitochondrial dysfunction may promote tumor progression by activating oxidative phosphorylation and PI3K/AKT signaling pathways. Furthermore, four proteins (i.e., SLC25A15, DIRAS2, PLA2R1, and MTARC1) associated with a TC poor prognosis have been recognized to be downregulated in PTMC with LNM; thus, they have been proposed as candidate biomarkers for predicting PTMC metastasis [ 28 ].…”

Expression profiling and bioinformatics analysis of serum exosomal circular RNAs in lymph node metastasis of papillary thyroid carcinoma

“…HIF-1 signaling pathway facilitated aggressive and progressive metastatic PTC by rewriting the glucose/iodine metabolic program in hypoxia microenvironment [31] . In addition, MAPK is present in various signaling pathways and broadly known to be involved in LNM of PTC [32] . Another important signal pathway, PI3K/Akt, was also analyzed to be closely related to multiple KEGG pathways, which functioned to thyroid tumorigenesis and progression by enhancing protein synthesis and overall reprogramming of cancer cell metabolism [33][34] .…”