Clinical significance of miR-144-ZFX axis in disseminated tumour cells in bone marrow in gastric cancer cases

• Published in: British journal of cancer Vol. 107; no. 8; pp. 1345 - 1353
• Main Authors: Akiyoshi, S, Fukagawa, T, Ueo, H, Ishibashi, M, Takahashi, Y, Fabbri, M, Sasako, M, Maehara, Y, Mimori, K, Mori, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-10-2012; Nature Publishing Group
• Subjects: 631/337/384/331; 631/67/322/803; 692/53/2422; 692/699/67/1504/1829; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Bone marrow; Bone Marrow - metabolism; Bone Marrow - pathology; Cancer Research; Clinical significance; Disease Progression; Diseases of the osteoarticular system; Drug Resistance; Epidemiology; Gastric cancer; Gene expression; Gene Expression Profiling; Hospitals; Humans; Kaplan-Meier Estimate; Kruppel-Like Transcription Factors - genetics; Medical research; Medical sciences; Metastasis; MicroRNAs; MicroRNAs - genetics; Molecular Diagnostics; Molecular Medicine; Neoplastic Cells, Circulating; Oligonucleotide Array Sequence Analysis; Oncology; Prognosis; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Surgery; Tumors; Tumors of striated muscle and skeleton; Japan; host cells; microRNA; disseminated tumour cell; cell fraction; RNA interference; Diseases of the osteoarticular system; Micro RNA; Malignant tumor; Stomach cancer; Gene silencing; Cancerology; Cell fraction; Bone tumor; Digestive diseases; Disseminated; Tumor cell; Cancer; Gastric disease
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2012.326

Background:
We previously reported that bone marrow (BM) was a homing site for gastric cancer (GC) cells leading to haematogenous metastases. There has been little study that microRNAs regulated pathways in malignant cells or host cells in BM, and thereby regulated the progression of GC.
Methods:
Both microRNA microarray and gene expression microarray analyses of total RNA from BM were conducted, comparing five early and five advanced GC patients. We focused on
miR-144
-
ZFX
axis as a candidate BM regulator of GC progression and validated the origin of the microRNA expression in diverse cell fractions (EpCAM
+
CD45
−
, EpCAM
−
CD45
+
, and CD14
+
) by magnetic-activated cell sorting (MACS).
Results:
Quantitative reverse-transcriptase (RT)–PCR analysis validated diminished
miR-144
expression in stage IV GC patients with respect to stage I GC patients (
t
-test,
P
=0.02), with an inverse correlation to
ZFX
(ANOVA,
P
<0.01). Luciferase reporter assays in five GC cell lines indicated their direct binding and validated by western blotting. Pre-
miR144
treatment and the resultant repression of
ZFX
in GC cell lines moderately upregulated their susceptibility to 5-fluorouracil chemotherapy. In MACS-purified BM fractions, the level of
miR-144
expression was significantly diminished in disseminated tumour cell fraction (
P
=0.0005). Diminished
miR-144
expression in 93 cases of primary GC indicated poor prognosis.
Conclusion:
We speculate that disseminated cancer cells could survive in BM when low expression of
miR-144
permits upregulation of
ZFX
. The regulation of the
miR-144
-
ZFX
axis in cancer cells has a key role in the indicator of the progression of GC cases.