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Sex-specific proteomic profiling identifies pregnancy zone protein as a complement-linked marker of adverse prognosis in esophageal adenocarcinoma

ABSTRACT: Esophageal adenocarcinoma (EAC) exhibits marked male predominance with male-to-female ratios reaching 8.5:1, yet the molecular basis underlying this sex disparity remains poorly characterized. We analyzed 92 EAC specimens using mass spectrometry–based proteomics, comprising 47 female and 45 male tumors from treatment-naïve patients. Differential expression, pathway enrichment, immunohistochemical, and survival analyses were used to identify sex-associated proteomic features and prognostic signatures. Proteomic profiling revealed focal yet biologically meaningful sex differences in esophageal adenocarcinoma. After multiple testing correction, three proteins were differentially expressed: the autosomal protein pregnancy zone protein (PZP), enriched in female tumors, and the Y-chromosome–encoded proteins DDX3Y and RPS4Y1, which were overexpressed in male tumors. At nominal significance, proteins upregulated in female tumors showed marked enrichment of immune-related pathways. Proteins correlated with PZP expression formed a network dominated by complement cascade. Clinically, elevated PZP expression was associated with significantly poorer overall survival, most pronounced in male patients and independent of sex-specific survival differences. Proteome-wide survival analyses further demonstrated distinct sex-specific prognostic landscapes. Our study provides the first comprehensive characterization of sex-associated proteomic differences in EAC. Sex shapes immune-related pathways, prognostic proteomic signatures, and survival associations. PZP emerges as a sex-differential, complement-associated protein with adverse prognostic significance, highlighting sex as a biologically and clinically relevant variable in EAC

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ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Proteomics Facility

LAB HEAD: Prof. Dr. A. Quaas

PROVIDER: PXD078617 | Pride | 2026-06-25

REPOSITORIES: Pride

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			Action	DRS
	4148-HUMANc-mbr-lib.tsv	Tabular
	4148-HUMANc-mbr-lib.tsv.speclib	Tabular
	4148-HUMANc-mbr.log.txt	Txt
	4148_Experiment_PRIDE.xlsx	Xlsx
	4148_rawFile.zip	Other

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Project description:A series of two color gene expression profiles obtained using Agilent 44K expression microarrays was used to examine sex-dependent and growth hormone-dependent differences in gene expression in rat liver. This series is comprised of pools of RNA prepared from untreated male and female rat liver, hypophysectomized (‘Hypox’) male and female rat liver, and from livers of Hypox male rats treated with either a single injection of growth hormone and then killed 30, 60, or 90 min later, or from livers of Hypox male rats treated with two growth hormone injections spaced 3 or 4 hr apart and killed 30 min after the second injection. The pools were paired to generate the following 6 direct microarray comparisons: 1) untreated male liver vs. untreated female liver; 2) Hypox male liver vs. untreated male liver; 3) Hypox female liver vs. untreated female liver; 4) Hypox male liver vs. Hypox female liver; 5) Hypox male liver + 1 growth hormone injection vs. Hypox male liver; and 6) Hypox male liver + 2 growth hormone injections vs. Hypox male liver. A comparison of untreated male liver and untreated female liver liver gene expression profiles showed that of the genes that showed significant expression differences in at least one of the 6 data sets, 25% were sex-specific. Moreover, sex specificity was lost for 88% of the male-specific genes and 94% of the female-specific genes following hypophysectomy. 25-31% of the sex-specific genes whose expression is altered by hypophysectomy responded to short-term growth hormone treatment in hypox male liver. 18-19% of the sex-specific genes whose expression decreased following hypophysectomy were up-regulated after either one or two growth hormone injections. Finally, growth hormone suppressed 24-36% of the sex-specific genes whose expression was up-regulated following hypophysectomy, indicating that growth hormone acts via both positive and negative regulatory mechanisms to establish and maintain the sex specificity of liver gene expression. For full details, see V. Wauthier and D.J. Waxman, Molecular Endocrinology (2008) This series is comprised of pools of liver RNA prepared from untreated male, hypophysectomized (‘Hypox’) male, untreated female and Hypox female rats (3-4 livers/pool), as well as liver RNA prepared from Hypox male rats treated with a single growth hormone injection and killed either 30, 60, or 90 minutes later (pool of n = 4 livers) or from Hypox male rats treated with two growth hormone injections spaced 3 or 4 hr apart (pool of n = 5 livers). The pools were paired to generate the following 6 direct microarray comparisons: 1) untreated male liver vs. untreated female liver; 2) Hypox male liver vs. untreated male liver; 3) Hypox female liver vs. untreated female liver; 4) Hypox male liver vs. Hypox female liver; 5) Hypox male liver + 1 growth hormone injection vs. Hypox male liver; and 6) Hypox male liver + 2 growth hormone injections vs. Hypox male liver. Dye swapping experiments were carried out for each of the six hybridization experiments, as follows. The Alexa 555-labeled cDNA from one of the two untreated male pools was mixed with the Alexa 647-labeled cDNA from one of the two untreated female pools. Similarly, Alexa 647-labeled cDNA from the second untreated male pool was mixed with the Alexa 555-labeled cDNA from the second untreated female pool. Together, these two mixed cDNA samples comprise a fluorescent reverse pair (dye swap). Dye swaps were similarly carried out for each of the five other competitive hybridization experiments, except that for experiments 5 and 6, a single pool of M-Hypox + GH liver cDNA, or a single pool of M-Hypox + 2GH liver cDNA, was used in each half of the fluorescent reverse pair. Two microarrays, one for each mixed cDNA sample, were hybridized for each of the six fluorescent reverse pairs, giving a total of 12 microarrays.

Project description:CLAMP transcription factor is a GA binding protein that recruits the male dosage compensation complex MSL to male X-chromosome, thus upregulating transcription level twice that of female X-chromosomes. Interestingly, CLAMP is essential for survival of both male and female individuals. However, what function it plays at the autosomes, especially in females is not known. It is well establised that GA-rich sequences to which CLAMP bind have evolved from polypyrimidine tracts that regulate splicing. Also, MALDI-MS data shows that CLAMP binds to RNA binding proteins involved in sex-specific splicing like, Squid. Furthermore, as part of MSL complex CLAMP interacts with MLE, a RNA helicase which is a known component of spliceosome complex conserved from flies to humans. Thus, we hypothesized that CLAMP plays a role in sex-spcific splicing. Given that CLAMP is a transcription factor, understanding mechanism of how it regulates splicing will add to our understanding about how regulators of gene expression shape the transcriptome differentially between males and females. We tested our hypothesis by identifying CLAMP dependent female and male sex-specific splicing events by analysing RNA-seq data from control as well as clampnull mutant male and female third instar larvae (L3) using suppa based time2splice pipeline (https://github.com/ashleymaeconard/time2splice). We identified 189 and 211 CLAMP dependent splicing events in female and male L3. Out of these 139 were female sex-specific splicing whereas 161 was male-sex-specific splicing. 50 splicing events identified as CLAMP dependent were non-specific to any particular sex, and were affect in both the sexes. Interestingly, we identified splicing of master regulator of sex-determination sxl affected by absence of CLAMP in females whereas splicing of one of the sex-determination pathway effectors, tra regulated by CLAMP in males. These findings indicate CLAMP plays important role in determining sex-specific transcript diversity in Drosophila.

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Sex-specific proteomic profiling identifies pregnancy zone protein as a complement-linked marker of adverse prognosis in esophageal adenocarcinoma

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