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Meng et al. J Cancer Metastasis Treat 2019;5:21 I http://dx.doi.org/10.20517/2394-4722.2018.96 Page 3 of 7

Figure 1. Mechanisms of alternative splicing of CD44 in epithelial-mesenchymal transition and breast cancer metastasis were summarized

and the formation of tumor microenvironment. Alternative splicing can produce various isoforms of CD44
with properties at different specific tissue [16,17] . The RNA-binding protein hnRNPM was found to promote
breast cancer metastasis by activating the switch of alternative splicing during EMT.

HNRNPM INCREASES CD44 ALTERNATIVE SPLICING TO ENHANCE BREAST CANCER
METASTASIS
CD44 was identified as a key downstream target of hnRNPM by genome-wide deep sequencing analysis.
hnRNPM is associated with increased standard form of CD44 (or CD44 standard, CD44s) in aggressive
breast cancer patient specimens. Overexpressed hnRNPM competes with epithelial splicing regulatory
protein 1 (ESRP1), and binds to the same cis-regulatory RNA elements of CD44 for the precisely control
[18]
CD44s splice isoform switching during EMT . ESRP1 is a splicing regulator to promote an epithelial
[19]
splicing program and hnRNPM is a mesenchymal splicing regulator. Harvey et al. reported that
hnRNPM and ESRP1 co-regulate a set of cassette exon events in EMT genes associated with cell migration
and cytoskeletal reorganization. Competitive binding to these cis-elements by hnRNPM and ESRP1 to
antagonize alternative splicing was proposed. The expression of hnRNPM is closely correlated with invasion
and metastasis of tumor cells. hnRNPM expression was upregulated in breast cancer tissues. HnRNPM and
CD44s expression are positively correlated in breast cancer tissues. Cancer stem cells marker ALDH1+ was
found positively associated with overexpression of CD44s and hnRNPM. High hnRNPM is associated with
higher levels of CD44s, shorter overall survival and higher rates of lymph node metastases in breast cancer
[20]
patients .

MORC2-MUTANT M276I PROMOTES AN HNRNPM-MEDIATED CD44 ALTERNATIVE SPLICING
TO ENHANCE BREAST CANCER METASTASIS
A cancer-associated Microrchidia family CW-type zinc finger 2 (MORC2) (M276I) mutant was reported to
promote metastatic ability of TNBC cancer cells by enhancing interaction with hnRNPM and splicing switch
of CD44 from the epithelial isoform (CD44v) to the mesenchymal isoform (CD44s) [Figure 1]. Expression of
mutant MORC2 in TNBC cells increased cell migration, invasion, and lung metastasis. The M276I mutation
enhanced binding of MORC2 to hnRNPM, a component of the spliceosome machinery. This interaction
promoted an hnRNPM-mediated splicing switch of CD44 from CD44v) to CD44s, ultimately driving EMT.
Knockdown of hnRNPM reduced the binding of mutant MORC2 to CD44 pre-mRNA and reversed the
mutant MORC2-induced CD44 splicing switch and EMT. As a consequence, the migratory, invasive, and
[21]
lung metastatic potential of mutant MORC2-expressing cells was impaired .