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Page 12 of 14 Schwertheim et al. Hepatoma Res 2020;6:41 I http://dx.doi.org/10.20517/2394-5079.2020.23

and in both the cytosol and the nucleus; they suppose that methylation/demethylation plays a role in
modulating β-catenin activity. Henderson et al. described that β-catenin can be exported from the nucleus
[29]
to the cytoplasm where its levels are regulated by degradation . Our results suggest that methylation of
β-catenin by KDM2A and consequently, repressing of Wnt/β-catenin signaling might play a role in the
beneficial survival of patients with immunopositive inclusions and cytoplasm. However, mechanistically
driven experiments are necessary to prove this hypothesis. The role of KDM2A in disease is contradictory
[30]
[26]
and seems to be context dependent . On one hand, KDM2A is upregulated in ovarian , breast and lung
[32]
cancer [13,30,31] and associated with a poor prognosis; on the other, it is downregulated in prostate cancer
and in the liver, KDM2A regulates hepatic gluconeogenesis whereby its exogenous expression reduces
[33]
blood glucose levels . Reasons for the dual effects of KDM2A may be due to the involvement of KDM2A
in various biological signaling pathways, including interacting with the p53-binding protein and NF-
[34]
kappaB activity by demethylation of the p65 subunit of NF-kappaB . Further, we found that the increased
occurrence of NI was significantly associated with KDM2A immunopositivity in NI. KDM2A is described as
[32]
a heterochromatin-associated and HP1-interacting protein and KDM2A is required to sustain centromeric
[32]
integrity and genomic stability, particularly during mitosis . A change in chromatin stability has been
discussed as a factor contributing to the development of NI [6,16,35,36] . Thus, we suppose that KDM2A might
play a role in the formation of inclusions. The mechanisms that participate in the formation of inclusions are
still poorly understood, in spite of several investigations [35,37] . However, we believe that various factors can
induce the formation of inclusions and that KDM2A may be one.

In this study, we demonstrated accumulations of β-catenin and proteins associated with the Wnt/β-catenin
pathway in NI. The simultaneous presence of β-catenin with autophagy-associated proteins, partly co-
localized to the same inclusion suggests that biological processes similar to autophagy might take place in
NI. Further, we found that the presence of KDM2A immnuopositive NI provides a survival benefit to HCC
patients. To what extent this is related to possible degradation of β-catenin by KDM2A, and whether NI play
a role in these biological processes needs to be analyzed by further experiments.

DECLARATIONS
Acknowledgments
We thank Dorothe Möllmann (Institute of Pathology, University Hospital of Essen, University of Duisburg-
Essen) for her excellent technical assistance. Additionally, the authors thank Laura Malkus (Institute of
Pathology, University Hospital of Essen, University of Duisburg-Essen) for technical assistance in the
preparation of the samples for TEM.

Authors’ contributions
Made substantial contributions to conception and design of the study and performed data analysis and
interpretation: Schwertheim S, Baba HA, Jastrow H, Herold T
Conceptualization: Schwertheim S, Baba HA, Schmid KW
Data acquisition: Herold T, Jastrow H, Baba HA, Schmid KW
Investigation: Schwertheim S, Theurer S, Jastrow H, Herold T, Ting S, Kälsch J, Baba HA, Schmid KW
Methodology: Schwertheim S, Theurer S, Jastrow H, Herold T, Ting S, Kälsch J, Baba HA
Supervision: Schwertheim S, Baba HA, Schmid KW
Writing - original draft preparation: Schwertheim S, Baba HA
Writing - review and editing: Schwertheim S, Theurer S, Jastrow H, Herold T, Ting S, Kälsch J, Baba HA,
Schmid KW

Availability of data and materials
The source of the data came from the Institute of Pathology, University Hospital of Essen.