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CANCER STEM CELLS AND

ONCOLOGY RESEARCH

International Conference on

Journal of Medical Oncology and Therapeutics

Volume 3

Jiangwen Zhang et al., J Med Oncl Ther 2018, Volume 3

INTEGRATED ANALYSES IDENTIFY

A POOR-PROGNOSIS SUBTYPE OF

HEPATOCELLULAR CARCINOMA

REGULATED BY A CORE microRNA

REGULATORY CIRCUITRY

Jiangwen Zhang, Qingzheng Kang, Yin Tong, Jianlong Sun

and

Xin-Yuan Guan

The University of Hong Kong, China

ancer stem cells (CSCs) cause tumor heterogeneity, relapse, and

resistance to therapy. The underpinnings of CSCs remain to be

elucidated, especially the underlying gene regulatory network. We here

conducted integrated analyses and identified a miRNA-regulatory

network defining a stemness subtype with poor-prognosis from TCGA

hepatocellular carcinoma (HCC) cohort with independent validations. The

poor-prognosis subtype was characterized by the signature expression

pattern of CSCs orchestrated by two miRNAs and their mRNA targets

that formed a core regulatory circuitry (CRC). Within the CRC, miR483-

3p bound a complementary sequence on

SOX9

promoter, facilitating the

recruitment of RNA polymerase II and STAT3, which was essential for

SOX9

transcription activation. SOX9 can further activate

SOX4

expression.

Both

SOX4

and its associated activator lncSOX4 were the direct targets

of miR204-5p.

SOX4

and miR204-5p formed double-negative feedback

loop through mutual inhibition. The expression level of miR204-5p was

tightly modulated by miR483-3p, whose promoter was significantly de-

methylated in the stemness subtype. Activation of the CRC essential

for the self-renewal and maintenance of liver CSCs culminated in

downregulation of miR204-5p and upregulation of miR483-3p,

SOX9

and

SOX4

. Functional significance of the CRC for HCC metastasis and

drug resistance was further demonstrated with various

in vitro

and

in vivo

assays.

Jiangwen Zhang graduated from Johns Hop-

kins University with PhD He has worked at

Harvard University Genome Center as Senior

System Biologist for years before joining Uni-

versity of Hong Kong in 2013. His lab has broad

interest in genetic and epigenetic regulation in

development and diseases. Currently, his lab is

focusing on epigenetic regulation of tumorigen-

esis. His lab employs high through-put ‘omics’

assays and large scale computation to dissect

the gene regulatory network and signaling path-

ways involved in oncogenesis.

jzhang1@hku.hk

BIOGRAPHY