Correlation of histopathologic characteristics to protein expression and function in malignant melanoma

Abstract

BackgroundMetastatic melanoma is still one of the most prevalent skin cancers, which upon progression has neither a prognostic marker nor a specific and lasting treatment. Proteomic analysis is a versatile approach with high throughput data and results that can be used for characterizing tissue samples. However, such analysis is hampered by the complexity of the disease, heterogeneity of patients, tumors, and samples themselves. With the long term aim of quest for better diagnostics biomarkers, as well as predictive and prognostic markers, we focused on relating high resolution proteomics data to careful histopathological evaluation of the tumor samples and patient survival information.Patients and methodsRegional lymph node metastases obtained from ten patients with metastatic melanoma (stage III) were analyzed by histopathology and proteomics using mass spectrometry. Out of the ten patients, six had clinical follow-up data. The protein deep mining mass spectrometry data was related to the histopathology tumor tissue sections adjacent to the area used for deep-mining. Clinical follow-up data provided information on disease progression which could be linked to protein expression aiming to identify tissue-based specific protein markers for metastatic melanoma and prognostic factors for prediction of progression of stage III disease.ResultsIn this feasibility study, several proteins were identified that positively correlated to tumor tissue content including IF6, ARF4, MUC18, UBC12, CSPG4, PCNA, PMEL and MAGD2. The study also identified MYC, HNF4A and TGFB1 as top upstream regulators correlating to tumor tissue content. Other proteins were inversely correlated to tumor tissue content, the most significant being; TENX, EHD2, ZA2G, AOC3, FETUA and THRB. A number of proteins were significantly related to clinical outcome, among these, HEXB, PKM and GPNMB stood out, as hallmarks of processes involved in progression from stage III to stage IV disease and poor survival.ConclusionIn this feasibility study, promising results show the feasibility of relating proteomics to histopathology and clinical outcome, and insight thus can be gained into the molecular processes driving the disease. The combined analysis of histological features including the sample cellular composition with protein expression of each metastasis enabled the identification of novel, differentially expressed proteins. Further studies are necessary to determine whether these putative biomarkers can be utilized in diagnostics and prognostic prediction of metastatic melanoma.

Phosphoproteomic insights into processes influenced by the kinase-like protein DIA1/C3orf58

“…Functional analysis of lists of proteins was performed using the DAVID and Panther servers ( Huang, Sherman & Lempicki, 2009 ; Mi et al, 2013 ). Overrepresentation of specific functional annotations within the lists was determined by Fisher’s exact test as described previously ( Welinder et al, 2017 ). Gene Ontology annotations, SwissProt keywords, and KEGG pathways were used as annotation terms for the enrichment analysis.…”

PD‐L1 expression by tumor cell lines: A predictive marker in melanoma

“…Moreover, upon IFN‐γ stimulation, we observed that the decreased expression of tyrosinase was associated with an improved RFS and the decreased expression of gp100 to an improved OS, whereas the decreased expression of Melan‐A was associated with a decreased OS. Our conflicting results regarding the predictive value of MAA perfectly illustrates the fact that data on this subject are controversial . Finally, we report that the unmodified MCSP expression in IFN‐γ‐treated melanoma cell lines was related to both increased RFS and OS.…”

Dynamic changes in the urine proteome of tumor-bearing mouse models of B16 melanoma and RM-1 prostate cancer

“…Melanoma cell adhesion molecule (Mel-CAM) has been shown to be a sensitive marker for epithelioid melanoma [44]; (7) Nuclear transport factor 2 plays an important role in the transport process mediated by the cargo receptor and plays a more general role indirectly. RanBP3 (a potential target for human melanoma therapeutic intervention) regulates melanoma cell proliferation through selective control of nuclear export [45]; (8) Eukaryotic translation initiation factor 6 modulates cell cycle progression and global translation of pre-B cells, and its activation seems to be rate-limiting in tumorigenesis and tumor growth [46] and is positively correlated with tumor tissue content in patients with metastatic melanoma [47]; (9) Disintegrin and metalloproteinase domain-containing protein 9 cleaves and releases many molecules that play important roles in tumorigenesis and angiogenesis and are potential tumor targets [48]. The protein is specifically expressed in stromal fibroblasts and can regulate the proliferation and apoptosis of melanoma cells in vitro and in vivo [49], and its expression is helpful for melanoma invasion [50];…”