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PLODs are overexpressed in ovarian cancer and are associated with gap junctions via connexin 43

Abstract

Procollagen-lysine, 2-oxoglutarate 5-dioxygenases (PLODs) play important roles in cancer progression, but their role in ovarian cancer remains elusive. In silico analysis of expression of PLODs in ovarian cancer was performed with reproduction of The Cancer Genome Atlas dataset. PLOD-enriched pathways and related gene(s) were validated by immunohistochemistry (IHC) in 80 ovarian cancer tissue blocks and in vivo xenograft murine models. PLODs (PLOD-1, -2, and -3) were overexpressed in ovarian cancer tissue. Overexpression of individual PLODs showed mutual exclusivity. Each of the three PLODs was differentially expressed between normal and cancer tissue of the ovary. PLOD1 was not prognostic, whereas lower PLOD2 and higher PLOD3 expression were associated with worsened prognosis, respectively. Cases with PLOD overexpression showed enrichment in gap junctions. GJA1 (connexin 43) was significantly overexpressed in cases with PLOD overexpression. IHC in tissue showed the strongest positive correlation between PLOD3 and connexin 43 expression, followed by PLOD2. As per Harmonizome, we selected SKOV3 and CAOV3 cell lines based on constitutive high PLOD1 and PLOD2/PLOD3 expression, respectively for in vitro and in vivo modeling. Only knockdown of PLOD3 was significantly associated with decreased GJA1 expression level in both cell lines. IHC in murine xenograft tumors also showed significantly lower connexin 43 in PLOD3-KD SKOV3 tumors. We conclude that PLODs are generally overexpressed in ovarian cancer and each PLOD may be functionally non-redundant. Association between PLOD3 and gap junctions warrants further investigation.

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Fig. 1: PLODs were overexpressed in ovarian cancer.
Fig. 2: Expression of PLOD3 and GJA1 was positively correlated.

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Funding

National Natural Science Foundation of China, Grant/Award Number: 81602288; National Key R&D Program of China, Grant/Award Number: 2016YFC1303100; Research project of Shanghai Municipal Health and Family Planning Commission, Grant/Award Number: 20174Y0046.

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TG and CX designed the study. TG, CG, and BL conducted experiments. TG performed statistical analysis. TG and CG drafted manuscript. All authors proof-read the manuscript.

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Correspondence to Congjian Xu.

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Guo, T., Gu, C., Li, B. et al. PLODs are overexpressed in ovarian cancer and are associated with gap junctions via connexin 43. Lab Invest 101, 564–569 (2021). https://doi.org/10.1038/s41374-021-00533-5

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