fluorescence microscopy. Analysis with an antibody against the carboxyl terminus of PRKACA
revealed a fluorescent signal that was consistently
brighter throughout the cells in FL-HCC (Fig. 3E
and fig. S1) than in the adjacent tissue normal
liver (Fig. 3D).
In summary, we have provided evidence for a
400-kb heterozygous deletion on chromosome
19 in 10 out of 10 FL-HCC patients tested. We
detected a chimeric DNAJB1-PRKACA RNA transcript in 12 of 12 patients tested and a putative
chimeric DNAJB1-PRKACA protein in 14 of 14
patients tested. The genomic deletion, the chimeric
transcript, and the chimeric protein were not
present in any normal liver samples tested. This
chimera is predicted to incorporate the J domain
of DNAJB1 and the catalytic domain of PRKACA.
The promoter is from the DNAJB1 gene, which
could explain why the chimeric transcript is expressed at higher levels than the WT PRKACA
transcript (Fig. 1, A, B, and C).
PKA is a heterotetramer composed of two
regulatory subunits and two catalytic subunits. In
this configuration, the catalytic subunit is inactive
until cAMP binding causes its release from the
regulatory units. The DNAJB1-PRKACA chimera
retains the functional catalytic domain and maintains full kinase activity, but it is missing the domain that binds the regulatory subunits of PKA.
PKA phosphorylates numerous cytoplasmic and
nuclear substrates, including members of the Ras,
mitogen-activated protein kinase (16), estrogen
signaling (17), and apoptosis pathways (18). PKA
is also involved in signaling via endothelial growth
factor receptor (19) and regulation of aromatase
expression (20), both of which can be overexpressed in FL-HCC (21–24). PRKACA has been
implicated in epithelial-mesenchymal transition,
migration, and invasion of lung cancer cells (25).
A review of publicly available data sets from the
Cancer Genome Atlas (26, 27) suggests that
PRKACA is amplified in 12% of ovarian serous
cystadenocarcinoma (28); 5% of uterine corpus
endometrial carcinoma (29); 3% of adenoid cystic
carcinoma (30); 2% of lung squamous cell carcinoma (31); 1% of sarcoma (32), colon and rectum
adenocarcinoma (33) and breast invasive carcinoma (34). In FL-HCC, the deletion we observe in
chromosome 19 has not been reported in comparative genomic hybridization of FL-HCC (35–38),
perhaps because of the limited resolution of the
approach at the time those studies were performed.
There are currently no molecular diagnostic
tests for FL-HCC. Because previous studies have
detected PKA in the peripheral blood of cancer
patients (39), this chimera may represent a diagnostic marker for FL-HCC. Surgical resection
remains the cornerstone of therapy and patients
who present with advanced-stage or metastatic
disease have few treatment options. While the
role of the DNAJB1-PRKACA chimera in the
pathogenesis of FL-HCC has yet to be addressed,
our observations raise the possibility that it contributes to the pathogenesis of the tumor and may
represent a therapeutic target.
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Acknowledgments: Two coauthors on this study are patients
with FL-HCC. We thank S. Tavazoie and H. Goodarzi for
trouble-shooting, recommending protocols and software, and
for helpful discussions of the data and the manuscript.
We thank R. Darnell for support, insightful discussions of
the data, and critical comments on the manuscript. We also thank
the Pathology core facility at Memorial Sloan-Kettering Cancer
Center (MSKCC), the Molecular Cytology core facility (MSKCC),
and members of the fibrolamellar community for support. This
work was funded by a grant from The Fibrolamellar Cancer
Foundation, The Rockefeller University Center for Clinical
and Translational Science grant 2UL1RR024143, and by an
anonymous donor. We thank J. Panda for fund-raising efforts.
C.N. T was supported by a Howard Hughes Medical Institute
International Student Predoctoral Fellowship. The New York
Genome Center and the authors (N.R., S.G., A.-K.E., and V.V.)
have filed a patent application related to the use of the chimeric
transcript in the detection of human cancers. Sequence data
have been deposited into the database of Genotypes and
Phenotypes, dbGaP (accession no. phs000709.v1.p1).
Materials and Methods
Tables S1 to S3
9 December 2013; accepted 29 January 2014
Chemical Warfare Among Invaders:
A Detoxification Interaction Facilitates
an Ant Invasion
Edward G. LeBrun,* Nathan T. Jones, Lawrence E. Gilbert
As tawny crazy ants (Nylanderia fulva) invade the southern United States, they often displace imported fire
ants (Solenopsis invicta). After exposure to S. invicta venom, N. fulva applies abdominal exocrine gland
secretions to its cuticle. Bioassays reveal that these secretions detoxify S. invicta venom. Further, formic
acid from N. fulva venom is the detoxifying agent. N. fulva exhibits this detoxification behavior after conflict
with a variety of ant species; however, it expresses it most intensely after interactions with S. invicta. This
behavior may have evolved in their shared South American native range. The capacity to detoxify a major
competitor’s venom probably contributes substantially to its ability to displace S. invicta populations, making
this behavior a causative agent in the ecological transformation of regional arthropod assemblages.
When multiple species invade a region, they often originate from common source assemblages (1). As a conse-
quence, species interactions in invaded regions
may reflect deep evolutionary histories. The
emerging invasion of the southern United States
by tawny crazy ants (Nylanderia fulva) and re-
sulting intense competitive conflict with red im-
ported fire ants (Solenopsis invicta) provide an
example of interacting invaders with shared evo-
lutionary histories. The native ranges of S. invicta
and N. fulva overlap in northern Argentina,
Paraguay, and southern Brazil (2–6), and within
this expansive region, these species compete di-
rectly for resources (7–9).
Since the 1930s, S. invicta has spread throughout the southern United States, ecologically dominating most grassland ant assemblages (10). In the
Brackenridge Field Laboratory, Department of Integrative Biology, The University of Texas at Austin, 2907 Lake Austin
Boulevard, Austin, TX 78703, USA.
*Corresponding author. E-mail: firstname.lastname@example.org.