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Sendino et al. Cancer Drug Resist 2018;1:139-63 I http://dx.doi.org/10.20517/cdr.2018.09 Page 145

The “XPO1 cancer exportome”

931 136 1577

XPO1 exportome Cancer-related genes
(Kirli et al. [34] , 2015) (Human Protein Atlas)

Figure 3. The “XPO1 cancer exportome”. The Venn diagram shows the overlap between the list of potential XPO1 cargos identified in
HeLa cells [34] and the group of “cancer related genes” defined in the Human Protein Atlas (v.18). The 136 overlapping proteins represent
what could be referred to as the “XPO1 cancer exportome”. The diagram was created using the jvenn web tool [208]

tivity of its transport signals (NLSs or NESs) or that create a novel signal in the mutant protein. For exam-
[67]
[68]
ple, aberrant localization of tumor suppressors BRCA2 and PALB2 to the cytoplasm can result from
mutations that unmask normally hidden NESs, whereas cytoplasmic mislocalization of certain NPM1
mutants is the result of a frameshift mutation that creates a novel strong NES, not present in the wild-type
[69]
protein .

On the other hand, a general defect in the nucleocytoplasmic localization of proteins (and RNA) may arise
in tumor cells, if elements of the transport machinery themselves are genetically altered or aberrantly ex-
pressed . Examples of genetic alterations targeting the nuclear transport machinery include chromosome
[70]
[71]
rearrangements involving nucleoporin genes (e.g., NUP98 and NUP214) in hematologic malignancies .
The abnormal fusion proteins resulting from these translocations have been reported to disrupt XPO1-
mediated export [72,73] . Examples of nuclear transport factors abnormally expressed in tumors include the
[64]
nuclear import receptors Importin β (see Dickmanns et al. and references therein) and Importina1 (see
[74]
Christiansen and Dyrskjøt , and references therein).
In the case of XPO1, both aberrant expression and genetic alterations have been detected in different types
of cancer, as detailed below. The abnormal XPO1 function that may result from these alterations would, in
turn, hinder the normal nucleocytoplasmic localization of hundreds of XPO1 cargo proteins. In the con-
text of the present review, those XPO1 cargos with a known role in the development of human tumors are
of particular interest. In this regard, we note that the extended list of potential XPO1 cargos identified in
[34]
HeLa cells by a recent high throughput analysis includes 136 members of the protein class “cancer-related
genes” registered in the Human Protein Atlas initiative (https://www.proteinatlas.org/) [Figure 3]. The set
of cancer-related proteins exported by XPO1 (which could be referred to as the “XPO1 cancer exportome”)
[75]
[76]
includes prominent tumor suppressors, such as p53 and BRCA1 , as well as protooncogenes, such as c-
abl . A more extensive account of cancer-related proteins that undergo XPO1-mediated nuclear export
[77]
can be found in previous reviews [10,65,66,78,79] .
Altered XPO1 expression in human tumors
The expression level of XPO1 at either the mRNA or protein level has been analyzed in many different
cancer types. As summarized in Table 1, XPO1 is frequently overexpressed in tumor samples with respect
to the corresponding normal tissue samples [80-99] . In fact, XPO1 overexpression was observed in all solid
[91]
tumor types and hematologic malignances examined, with the exception of liver cancer .