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. 2024 Aug;28(16):e70041.
doi: 10.1111/jcmm.70041.

Functional variants of the pentraxin 3 gene are associated with the metastasis and progression of prostate cancer

Wei-Chun Weng  1   2 , Yi-Hsien Hsieh  3   4 , Chia-Yen Lin  5   6   7 , Yu-Fan Liu  8 , Shih-Chi Su  9   10 , Shian-Shiang Wang  5   6   11 , Shun-Fa Yang  3   4
Affiliations

Functional variants of the pentraxin 3 gene are associated with the metastasis and progression of prostate cancer

Wei-Chun Weng et al. J Cell Mol Med. 2024 Aug.

Abstract

Age, ethnic background and genetic components have been identified as the established risks for prostate cancer (PCa). Pentraxin 3 (PTX3), originally identified as a pattern-recognition molecule for defence against infectious agents, has multiple functions in tissue repair and in the regulation of cancer-associated inflammation. In this study, we sought to investigate the impact of PTX3 gene variants on the development of PCa. Genotypes of four common single-nucleotide polymorphisms (SNPs) of PTX3 gene, including rs1840680, rs2305619, rs3816527 and rs2120243, were profiled among 705 PCa patients and 705 ethnicity-matched controls. In this study, we found that patients who carry at least one minor allele (C) of rs3816527 (AC and CC) tended to develop advanced forms of diseases (clinical large T stage, OR, 1.593, p = 0.032; pathologically-confirmed nodal spread, OR, 1.987, p = 0.011; metastatic tumour, OR, 3.896, p = 0.032) as compared with those homologous for the major allele (AA). Further stratification analysis showed that such association of rs3816527 with lymphatic and distal metastasis of PCa was accentuated in the younger age group (≤65 at diagnosis) but not seen in the older age group (>65 at diagnosis), suggesting an age-specific effect of PTX3 variants. Prediction of PTX3 protein structure implied that polymorphism may alter the quaternary organization and oligomerization of PTX3 protein. Moreover, our gene silencing experiments and survey of public datasets revealed that elevation of PTX3 levels in PCa was required for cell migration and associated with tumour metastasis. Our results highlight an association of PTX3 rs3816527 with the progression of PCa.

Keywords: metastasis; pentraxin 3; prostate cancer; single‐nucleotide polymorphism.

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Conflict of interest statement

The authors declare no conflicts of interest related to this study.

Figures

FIGURE 1
FIGURE 1
Conformational insights into the human variant (rs3816527) revealed the formation of the quaternary organization through altering orders of PTX3 protein structure. (A) Schematic representing the protein domains of PTX3 monomer (UniProt: P26022), highlighting the locations of cysteine bond networks. The closed loops illustrate the presence of intra‐monomeric disulfide bonds. C47/C49 could participate in intra‐ or inter‐subunit disulfide bonds, and C317/C318 in inter‐tetramer disulfide bonds to form PTX3 oligomerization states. Domain symbols are drawn approximately to scale. The numbering of residues is displayed in colour black. (B) Ribbon diagram (NGL viewer 2.0) for the 3D AlphaFold‐based predicted model of human PTX3 (https://alphafold.ebi.ac.uk/entry/P26022) includes the C‐terminal PTX domain core (Pfam: PF00354; blue) and the N‐terminal tetrameric coiled‐coil domain (red) that is connected by conserved cysteine sulfur bonds. (C) Enlarged view of the selected variant region, displayed in a similar orientation as shown in part (B). The representation used a ball‐and‐stick model and broken lines to mark the hydrogen‐bonding interactions between backbone groups.
FIGURE 2
FIGURE 2
Silencing of PTX3 gene impaired cell migration and clonogenic survival of PCa cells. (A) Basal levels of PTX3 in three PCa cell lines, whose rs3816527 genotypes were determined, were evaluated via immunoblotting. (B) PC‐3 cells transfected with vectors expressing control or PTX3‐specific siRNA were seeded in a modified Boyden chamber for measurement of cell migration. Quantitative data are shown underneath. *p < 0.05 as compared with scramble shRNA controls.
FIGURE 3
FIGURE 3
Comparison of PTX3 levels in PCa datasets from the Gene Expression Omnibus (GEO) repository. (A) PTX3 levels between PCa samples and adjacent normal prostate tissues in GSE59745. (B‐D) PTX3 levels between primary and metastatic PCa specimens in GSE8511 (B), GSE6919 (C), and GSE3325 (D). p‐values were calculated between two groups by Student's t‐test.
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