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. 2022 Jun 23;17(2):131.
doi: 10.3892/mco.2022.2564. eCollection 2022 Aug.

Impact of JMJD6 on intrahepatic cholangiocarcinoma

Yukiko Kosai-Fujimoto  1 , Shinji Itoh  1 , Kyohei Yugawa  1 , Takasuke Fukuhara  2 , Daisuke Okuzaki  3 , Takeo Toshima  1 , Noboru Harada  1 , Yoshinao Oda  4 , Tomoharu Yoshizumi  1 , Masaki Mori  1
Affiliations

Impact of JMJD6 on intrahepatic cholangiocarcinoma

Yukiko Kosai-Fujimoto et al. Mol Clin Oncol. .

Abstract

The association of Jumonji domain-containing 6 (JMJD6) with the prognosis of various types of cancer has been demonstrated, except in intrahepatic cholangiocarcinoma (ICC). The present study aimed to clarify the impact of JMJD6 on ICC. The liver specimens of 51 patients who underwent surgery for ICC were analyzed for JMJD6 expression using immunohistochemistry staining. The relationship between clinicopathological factors and JMJD6 expression was investigated. The cellular activity was also evaluated in JMJD6 knocked down cells with Transwell migration assay and viability assay. In the immunohistochemistry staining of clinical samples, high expression of JMJD6 was seen in 32 of 51 samples. High expression was also associated with improved overall survival (OS) and recurrence-free survival (RFS) (P=0.0033 and 0.048, respectively). Further analyses revealed that higher JMJD6 expression was one of the improved independent prognostic factors of OS and RFS. Expression of JMJD6 was knocked down in commercial culture cell lines of ICC, and RNA and protein were extracted to analyze the downstream gene expression using RNA-sequencing and western blotting. JMJD6 knockdown was associated with higher programmed death-ligand 1 (PD-L1) expression in RNA-sequencing and western blotting. In addition, PD-L1 expression was higher in JMJD6 low expression clinical samples when measured using immunohistochemistry staining. In conclusion, high expression of JMJD6 was an independent favorable prognostic factor of ICC. JMJD6 may influence the prognosis of ICC through the regulation of PD-L1 expression.

Keywords: JMJD6; PD-L1; cholangiocarcinoma; liver tumor.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
JMJD6 expression in clinical samples. (A) Representative images of high, intermediate and low JMJD6 expression in stained tissues (scale bar, 250 µm). (B) Number of samples for each staining rate and >35% of samples are marked as high expression. (C) Survival analysis of JMJD6 with overall survival. (D) Survival analysis of JMJD6 with recurrence-free survival curve. JMJD6, Jumonji-domain containing 6, MVI, microvascular invasion.
Figure 2
Figure 2
Expression of JMJD6 and PD-L1 in ICC cell lysates. (A) Migration assay with SSP-25 cells. Left: The bar chart of number of migrated cells. Right: The representative images of migration (scale bar, 500 µm). (B) Cell viability assay with SSP-25. (C) Volcano plot of RNA-sequencing results of SSP-25. (D) Bar chart of PD-L1 and JMJD6 expression. In the lysates of JMJD6-knockdown cells, PD-L1 was significantly overexpressed. (E) RT-qPCR of JMJD6-knockdown SSP-25 cell lysate. RT-qPCR demonstrated that PD-L1 expression was upregulated in the JMJD6-knockdown samples. (F) Western blotting of ICC cells after JMJD6-knockdown. The ICC cells showed the same expression patterns as the RNA analysis. *P<0.05. RT-qPCR, reverse transcription-quantitative PCR; ICC, intrahepatic cholangiocarcinoma; JMJD6, Jumonji-domain containing 6; si, short interfering; PD-L1, programmed death-ligand 1.
Figure 3
Figure 3
PD-L1 expression in ICC clinical samples. (A) Immunohistochemistry staining of PD-L1 with placenta as a positive control. (B) Representative images of positive staining. (C) Negative staining. (D) Relationship between positive JMJD6 and PD-L1 staining (scale bar, 250 µm). ICC, intrahepatic cholangiocarcinoma; JMJD6, Jumonji domain-containing 6; PD-L1, programmed death-ligand 1.
See this image and copyright information in PMC

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