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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 5 of 7

Non-coding RNAs (ncRNAs) RE1-silencing transcription factor (REST)-003 was reported to promote breast
cancer metastasis. REST-003 is cRNAs derived from the first exon of an alternatively spliced REST transcript
processed by serine/arginine repeat-related protein SRRM3. REST is a transcription factor to regulate
expression of genes important for neuronal development. Interestingly, SRRM3 expression is repressed by
[26]
REST .

MTDH PROMOTES BREAST CANCER METASTASIS PARTIALLY BY REGULATING
ALTERNATIVE SPLICING
High metadherin gene expression was highly correlated with breast cancer metastasis [27,28] . MTDH was
identified to bind to the vasculature of the lung by phage display screening cDNAs from metastatic breast
[27]
carcinoma . Experimental metastasis can be inhibited by metadherin specific antibody or siRNAs.
Hu et al reported that MTDH drives breast cancer metastasis to the lungs by increasing adhesion to the
[28]
walls of blood vessels . Amplification of a minimal 2.9 Mb piece of chromosome 8q22 was identified
in poor-prognosis breast cancers by ACE (analysis of CNAs by expression data) and fluorescence in situ
hybridization (FISH) analysis. Only the enforced expression of MTDH in this amplified 8q22 region was
identified to increase lung seeding after tail vein injection of the mildly metastatic breast cancer cell line
[28]
MDA-MB-231 . Interaction of MTDH with Staphylococcal nuclease domain-containing 1 (SND1) was
independently identified by mass spectrometry (MS) by three labs [29-31] . Overexpression of MTDH and
SND1 in primary tumors is strongly associated with reduced metastasis-free survival in multiple large-
scale datasets of breast cancer patients [32,33] . SND1 acts as a novel alternative splicing regulator by interacting
with SAM68 to regulate exon v5 inclusion in the CD44 mRNA splicing that promotes cancer metastasis
[Figure 1] [34-36] . Several other splicing regulators including hnRNPA0, hnRNPA2B1, hnRNPF, hnRNPA3
[29]
isoform were also identified by MS in MTDH pull-down assay . High-throughput sequencing of RNA
isolated by Cross-linking immunoprecipitation (HITS-CLIP) and Photoactivatable Ribonucleoside-
Enhanced Cross-linking and Immunoprecipitation (PAR-CLIP) were recently developed methods to study
RNA-protein interactions [37,38] . As shown in Table 1, mRNAs encoding for mRNA splicing regulators were
identified in MTDH RNA interactome for multiple times at different sites by MTDH antibody specific PAR-
[39]
CLIP and 12 splicing factors were confirmed by MTDH HITS-CLIP . Therefore, MTDH may promote
breast cancer metastasis by regulating mRNA splicing through interacting with mRNAs or proteins of
splicing factors.

CONCLUSION
Increased expression of mRNAs alternative splicing isoforms derived from alteration of splicing factors and
MTDH expression could promote EMT and breast cancer metastasis, which provides new targets for breast
cancer therapy.

DECLARATIONS
Authors’ contributions
Conception and elaboration of the work: Meng X, Yang S, Zhang J, Yu H
Provided administrative, technical, and material support: Meng X, Yang S, Zhang J, Yu H
Final approval of the version: Meng X, Yang S, Zhang J, Yu H

Availability of data and materials
Not applicable.

Financial support and sponsorship
The studies were supported from NIH (RO1CA184101) to Meng X.

Conflicts of interest