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J Cancer Metastasis Treat 2020;6:5 I http://dx.doi.org/10.20517/2394-4722.2020.13 Page 21 of 38
Results: We showed that tissue transglutaminase (TG2), a cancer stem cell survival and drug-resistance
protein, is highly enriched in human mesothelioma tumors and mesothelioma cancer stem cells (MCS
cells) and drives MCS cell spheroid formation, invasion, and migration. TG2 knockdown or TG2 inhibitor
treatment reduces MCS cell survival, spheroid formation, Matrigel invasion, migration, and tumor
formation. These are important observations as MCS cells comprise a highly aggressive subpopulation
of tumor that forms rapidly growing and aggressive tumors. In addition, transcriptome analysis reveals
that TG2 loss is associated with reduced levels of mRNA encoding a wide range of cancer stem cell and
epithelial-mesenchymal transition proteins, and that TG2 knockdown reduces expression of transcripts and
proteins encoding pro-cancer matrix proteins including collagens COL1A2 and COL3A1 that are involved
in metastasis. Mesothelin, a mesothelioma cell-specific MCS cell survival protein and attachment factor, is
also reduced in TG2 knockdown cells.
Conclusions: These studies indicate that TG2 is highly overexpressed in MCS cells and drives the cancer
stem cell phenotype to enhance MCS cell stemness, survival, and invasion, and suggests that TG2 is an
important candidate mesothelioma cancer stem cell therapy target.
29. Forward genetics to discover tumor suppressor in colorectal cancer
Tao Lu
Department of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Drive,
Indianapolis, IN 46202, USA.
The nuclear factor κB (NF-κB) plays pivotal roles in inflammatory and immune responses and in cancer.
Therefore, understanding its regulation holds great promise for disease therapy. Using validation-
based insertional mutagenesis, a powerful technique established by us, we discovered a novel negative
regulator of NF-κB (named NNRN1) in colorectal cancer (CRC). We showed that NNRN1 overexpression
downregulated the expression of NF-κB-dependent genes, many of which are related to cancer.
Additionally, compared to the vector control group, overexpression of NNRN1 in HEK293 cells or CRC
HT29, DLD1, and HCT116 cells dramatically reduced NF-κB activity, cellular proliferation, anchorage-
independent growth, and migratory ability in vitro, and, unsurprisingly, significantly decreased xenograft
tumor growth in vivo. In contrast, shNNRN1 knockdown cells showed the opposite effect. Furthermore,
co-immunoprecipitation (Co-IP) experiment confirmed that NNRN1 may form a complex with the p65
subunit of NF-κB. Importantly, immunohistochemistry data exhibited much lower NNRN1 expression
level in CRC patient tumor tissues compared to normal tissues, indicating that NNRN1 may function as a
tumor suppressor in CRC. To conclude, our findings for the first time uncovered the negative regulatory
function of NNRN1 in NF-κB signaling, and present NNRN1 as an innovative therapeutic target in CRC
treatment.
30. Immunogenic cell death in myeloid leukemia
Marc Diederich
College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
Background and aim: We investigated the effect of pharmacologically active compounds that act as
immunoadjuvants able to trigger a cancer stress response and release of damage-associated molecular
[1]
patterns (DAMPs) in myeloid leukemia . These processes result in a chemotherapeutic response with