SHINING A LIGHT ON THE GENOME’S ‘DARK MATTER’ NON-CODING RNAs (nc RNAs) : MICRORNAs AND CANCER...

SHINING A LIGHT ON THE GENOME’S ‘DARK MATTER’NON-CODING RNAs (nc RNAs) : MICRORNAs AND CANCER

SHINING A LIGHT ON THE GENOME’S ‘DARK MATTER’NON-CODING RNAs (nc RNAs) : MICRORNAs AND CANCER

MICRORNAs (MiRs) AND CANCERMICRORNAs (MiRs) AND CANCER

Outline of Presentation

• Non-coding RNAs (ncRNAs) and microRNAs (MiRs)-background and functions

• MiR expression in tumors and cancer cells

• MiRs as prognostic factors for cancer patients

• miRs in body fluids and their potential as prognostic and diagnostic biomarkers

• Examples of miR functions in cancer

• MiRs as drug targets

ncRNAs IN BACTERIAL AND EUKARYOTIC GENOMES % OF ncRNAs*

ncRNAs IN BACTERIAL AND EUKARYOTIC GENOMES % OF ncRNAs*

* From Szymanski and Barciszewski Genome Biol.3, 005.1, 2002

100%

50%

0%

1.4% 29% 27% 20% 70% 86% 91% 92%

Homo SapiensArabidopsis thaliana

Caenorhabditis elegans

Drosophila melanogaster

Saccharomyces cerevisiae

Escheichia coli

Mycobacterium tuberculosis

Archaeoglobus fulgidus

1 2 3 4 5 6 7 8

1

23

4

56

6

7

nc RNAs – “Dark Matter” Functionnc RNAs – “Dark Matter” Function

nc RNA*

long(>200 nt)

* Bioessays 32, 599, 2010; Cancer Res 71, 3, 2011

• chromatin association and

gene modulation/

silencing

small(20-300 nt)

microRNAs (~23 nt)

• decrease mRNA

stability/ translation

Piwi-interacting RNAs (piRNAs,

26-31 nt)

• gene silencing/ methylation

Promoter-associated RNAs (small/variable)

• gene silencing..?

many more

Long intergenic non-coding

RNAs (ncRNAs)

• miRs interact with 3’-UTR of mRNAs• Low miR-mRNA base specificity

(6-8)• Each miR can potentially interact

with several hundred mRNAs• Function: block gene expression

Pre-miRNA

MicroRNA REGULATION OF GENE EXPRESSION IN CANCER CELLS/TUMORS

MicroRNA REGULATION OF GENE EXPRESSION IN CANCER CELLS/TUMORS

20-22 nt

(single chain)

miR-27a

miR-27a

RNA

miR

COMPLEXITIES OF MiR-mRNA INTERACTIONS MULTIPLE MiRs REGULATE A SINGLE mRNA*

COMPLEXITIES OF MiR-mRNA INTERACTIONS MULTIPLE MiRs REGULATE A SINGLE mRNA*

• the p21 3’UTR can potentially be targeted by 266 miRs (p21 – tumor suppressor)

266-miRs

luc

Transfected

3’UTRp21

HEK293 cells

• 28 miRs interacted with 3’-UTR; decreased luciferase activity • overexpression of miRs decreased p21 protein and mRNA levels

“Oncogene 29, 2302, 2010”

MicroRNA ACTIVITY IN CANCER: TUMOR SUPPRESSIVE OR ONCOGENIC

MicroRNA ACTIVITY IN CANCER: TUMOR SUPPRESSIVE OR ONCOGENIC

miR

Tumor suppressive

Oncogenic

miR

• Suppress expression of oncogenes, growth promoting, survival and angiogenic genes (low in tumors)

• Suppress expression of tumor suppressor, growth inhibitory, proapoptotic genes (high in tumors)

INDIVIDUAL MiRs ASSOCIATED WITH MULTIPLE TUMORS

INDIVIDUAL MiRs ASSOCIATED WITH MULTIPLE TUMORS

miR TS/OG Tumors

Let-7 Family

MiR-159/16-1 cluster

MiR-17-92 cluster

MiR-26a

MiR-34a/b/c

MiR-21

TS

TS

OG

TS/OG

TS

OG

10

7

7

4

6

10

TS = tumor suppressor; OG = oncogene

SPECIFICITY OF MiR EXPRESSION IN TUMORS*SPECIFICITY OF MiR EXPRESSION IN TUMORS*

miR Tumor Tissue TS/OG

MiR-155

MiR-200/141 family

MiR-205

MiR-206

MiR-9

Hematopoietic system

Epithelial-specific

Epithelial-specific

Skeletal and muscle

Nervous system

OG

TS/OG

TS/OG

TS

TS/OG

TUMOR-SPECIFIC PATTERNS OF MiR EXPRESSION LIVER CANCER-CELL GROWTH/APOPTOSIS*


DOWNREGULATED UPREGULATED

let7 miR-1

c-Myc Bcl-XL

miR-101

c-Met FoxP1 McL-1 FOS

miR-122

cyclin G1

SRF

miR-101

CDK-6 cyclinD1

miR-124

CDK6

miR-199

mTOR c-Met cyclinD2

miR-283

cyclinE2

miR-2a

YAP

miR-106b-25

p21 Bim

APL-5p27

miR-124

p57

multiple

let7

ERa

miR-18a

PTEN

miR-21 miR-101

RASSFLA

miR-602

*Br.J.Cancer 104, 235, 2011 (partial list)



miRs

• Corresponding growth promoting/

prosurvival mRNAs- upregulated

• Corresponding growth inhibitory/anti-survival mRNAs-downregulated

miRs

CORRELATION OF MIR EXPRESSION WITH PROGRESSION AND PROGNOSIS OF GASTRIC CANCER*

CORRELATION OF MIR EXPRESSION WITH PROGRESSION AND PROGNOSIS OF GASTRIC CANCER*

PATIENTS: 181 patients from 2 cohorts (Japan)

CLASSIFICATION: Stages I-IV Diffuse vs. Intestinal type

ANALYSIS: • Custom miR microarray chip (Ohio State Univ.)

• miR expression in 160 paired samples (tumor vs. non-tumor)• Correlations of miR expression vs. stage, type and prognosis (survival)

* Lancet Oncol. 11,136, 2010

GASTRIC CANCER MiR SIGNATURE*GASTRIC CANCER MiR SIGNATURE*

UPREGULATED MIRs (22): miR-181 (6), miR-21, miR-25,miR-92 (2), miR-19b (2), miR-17-92 (7), miR-224, miR-19amiR-345, miR-191, miR-135b, miR-135a (2)

DOWNREGULATED MIRs (13): miR-148 (2), miR-375, miR-29b (2), miR-29c, miR-152, miR-218-2, miR-451, miR-30a-d (5), miR-422b

Several different miRs in the cluster. Lancet Oncol. 2010

MiRs AS PROGNOSTIC FACTORS: GASTRIC CANCER SURVIVAL*

MiRs AS PROGNOSTIC FACTORS: GASTRIC CANCER SURVIVAL*

0

1

2

3

4

5

StagesI-II

StagesIII-IV

3.2

high low high low low high01

2

34

5

67

89

10

Let-7g

miR-199

miR-495

HA

ZA

RD

RA

TIO

(dis

ea

se

fre

e s

urv

iva

l)

HA

ZA

RD

RA

TIO

(dis

ea

se

fre

e s

urv

iva

l)

Intestinal-Type Gastric Cancer

I-II III-IV I-II III-IV I-II III-IV

SERUM AND BODY FLUID MiRs AS BIOMARKERS

SERUM AND BODY FLUID MiRs AS BIOMARKERS

• Multiple miRs have been characterized not only in serum but also tears, urine, breast milk, seminal fluid, saliva, amniotic fluid, bronchial lavage, cerebrospinal fluid, pleural fluid, peritoneal fluid and colostrum

(Clin. Chem 56, 1733, 2010)

• A select number of miRs may serve as diagnostic markers for different tumor types

(Mol. Cancer 9:306, 2010)

SERUM MiRs AS MARKERS FOR LIVER PATHOLOGIES

(Clin. Sci 120, 183, 2011)

SERUM MiRs AS MARKERS FOR LIVER PATHOLOGIES

(Clin. Sci 120, 183, 2011)

• Elevated in sera from patients with liver pathologies

• Primarily expressed in liver

• Function - not known

8

6

4

2

10

Rel

. miR

-885

-5p

Exp

r

Normal Hepato-cellular

Carcinoma

Livercirrhosis

MiR-885-5pSerumMiR-885-5p Levels

MiRs AS PROGNOSTIC FACTORS FOR CANCER: SUMMARY

MiRs AS PROGNOSTIC FACTORS FOR CANCER: SUMMARY

• There are unique miR signatures for different cancers

• Several miRs are up-or downregulated in multiple tumors

• Tumors and serum miR expression can be prognostic factors for patient survival

• Since multiple miRs target unique and overlapping mRNAs, are there functional individual miRs and can they be targeted by anticancer agents?

EXAMPLES OF FUNCTIONAL MiRs IN TUMORS

EXAMPLES OF FUNCTIONAL MiRs IN TUMORS

• Highly expressed in multiple tumorsmiR-21• Modulates expression of apoptotic/growth

inhibitory mRNAs

• Highly expressed cluster in multiple tumorsmiR-17-92• Several paralogs (same seed sequence)

modulate expression of anti-carcinogenic mRNAs

• Low expression in tumorsmiR-335• Expression studies suggest that miR-335

inhibits metastasis

MiR-21 IS ONCOGENIC IN VITROMiR-21 IS ONCOGENIC IN VITRO

• Multiple studies show that knockdown of miR-21 in cancer cells decreases growth and induces apoptosis

• Overexpression of miR-21 in cancer cells enhances their tumorigenicity

• miR-21 is a prognostic factor for poor patient survival

• miR-21 also plays a role in drug-resistance

MiR-21 IS A NEGATIVE PROGNOSTIC FACTOR FOR PANCREATIC CANCER PATIENTS*

MiR-21 IS A NEGATIVE PROGNOSTIC FACTOR FOR PANCREATIC CANCER PATIENTS*

0

50

100 low miR-21

high miR-21

0

20

Ov

era

ll S

urv

iva

l (M

o)

% o

f p

ati

en

ts

Radically resected

metastatic

Grade 1-2 3

(1000X higher in tumor vs. non-tumor tissue)

*Cancer Res 70, 4528, 2010; PLOS One 5, e10630, 2010

• Patients were treated with gemcitabine

• miR-21 also linked to gemcitabine and drug resistance (5-FU)

ONCOMIR-21: IN VIVO TRANSGENIC MICE OVEREXPRESSING MIR-21

(Nes Cre 8, miR-21LSL-Tetoff) (DOXYCYCLINE )

ONCOMIR-21: IN VIVO TRANSGENIC MICE OVEREXPRESSING MIR-21

(Nes Cre 8, miR-21LSL-Tetoff) (DOXYCYCLINE )

• Overexpression of miR-21 in mice results in pre-B malignant lymphoid tumors

• Doxycycline-induced downregulation of miR-21 inhibits oncogenesis

Mice with lymphomas (+) Doxycycline

(-) Doxycycline

Age (days)100

100

Su

rviv

al (

%)

ONCOMIR-21: IN VIVO KNOCK OUT STUDIESONCOMIR-21: IN VIVO KNOCK OUT STUDIES

*Cancer Cell 18, 282, 2010 PNAS 108, 10144, 2011

• No obvious phenotype in miR-21-/- mice

• Decreased DMBA-induced skin cancer (miR-21-/-)

• miR-21-/- suppresses K-ras induced lung cancer

0

10

20

Lung Tumors

0

3L

es

ion

s/L

un

g

Re

l. T

um

or

Are

as

Adenoma

K-RasLA2 K-RasLA2

miR-21-/-

K-RasLA2 K-RasLA2

miR-21-/-

REGULATION OF SPECIFICITY PROTEIN (Sp) TRANSCRIPTION FACTORS BY MiRs (ONCOMIRS)


•Low expression

in non tumor tissue

•High expressionin tumor tissue

Mechanisms for Sp overexpression

• Epigenetic effects (hypo/hypermethylation)

-no evidence

• Enhanced expression of genes that regulate Sp TFs

-they are self regulatory

• Inhibition of “Sp repressors”……..by miRNAs?



5 microRNAs (miRs)

as-MiR-27a ZBTB10 (1.4 Fold)

SKBR3

CELLS

LAQ824

(HDACi)5 hr

+

22 miRs (including miR-27a)

-

+

Note:miR-27a

ZBTB10mRNA

One of several hundred potential

miR-27a target

Cancer Res. 66, 1277,2006



MiR-27a : ZBTB10?

• ZBTB10 competitively binds (and displaces Sp) GC rich sequences (JBC 274, 8123, 1999)

• ZBTB10 is a member of the BTB/POZ family of transcription repressors

• Does miR-27a repress ZBTB10 and thereby allow for overexpression of Sp1, Sp3 and Sp4?



ZBTB10 – an Sp repressor

High Basal Sp Expression in Tumors

miR-27a

ZBTB10

LOW

ZBTB10

low

HIGH

Sp

SpSp

SpSp

Sp

GC

EGFR, CD1, c-Met

(growth)

bcl-2, survivin

(survival)

VEGF, VEGFR1VEGFR2

(angiogenesis)

NFkB,p65

(inflammation)



(a) Cancer Res. 67 11011, 2007

miR-17-5pmiR-20a

ZBTB4

(a) Oncogene 2012

ZBTB4

mitochondria

ROSmiR-20amiR-27a

Sp-repressor (mRNA)

EGFR, CD1, c-Met (growth)

bcl-2, survivin(survival)

VEGF, VEGFR1/VEGFR2

(angiogenesis)

NFkB/p65(inflammation

Mechanisms of drug-induced repression of Sp1, Sp3, Sp4 and Sp-regulated genes in cancer cell lines (curcumin, celastrol, aspirin, betulinic acid….)

ZBTB10ZBTB4

SUMMARY OF ONCOMIRS THAT SUPRESS Sp TRANSCRIPTION FACTORS

SUMMARY OF ONCOMIRS THAT SUPRESS Sp TRANSCRIPTION FACTORS

phosphatases

proteasomes

caspases (active)

Sp- regulated genes

•Several anticancer drugs downregulate miRs and induce Sp repressors which downregulate Sp1, Sp3 and Sp4 genes.

•Can anticancer drugs induce tumor suppressor-like miRs ?

DEVELOPMENT OF ANTICANCER DRUGS THAT TARGET MiRS

DEVELOPMENT OF ANTICANCER DRUGS THAT TARGET MiRS

inhibition

ER

ER

EEstrogenic Responses

Inhibited by AhR-ER Crosstalk• Mammary tumor formation

and growth (rodent & human)DR

E

TCDD ( )

2,3,7,8-TCDD AS AN ANTIESTROGEN2,3,7,8-TCDD AS AN ANTIESTROGEN

• Uterine and endometrial responses (rodents)

• Breast cancer cell responses

AhR

arnt ER

AhR arnt

O

OCl

Cl

Cl

Cl

Ah RECEPTOR AS A DRUG TARGETAh RECEPTOR AS A DRUG TARGET

DRE

Drug

*Toxic responses (chloracne, wasting…)

*Biochemical responses (CYPlA, UGT/GST…)

*Pharmacolologic responses (antiestrogenicity, anticancer activity, autoimmune diseases)

*Age, sex, species, strain and tissue-dependent

AhR arnt

O

1,3,6,8-

O

Alternate-substitutedAlkyl PCDFs (synthetic)

2,4,6,8-

NH

CH2OH

Indole-3-carbinol (I3C)

NH

2

CH2

Diindolylmethane (DIM)

DEVELOPMENT OF NON-TOXIC AhR-BASED ANTIESTROGENS

DEVELOPMENT OF NON-TOXIC AhR-BASED ANTIESTROGENS

• moderate AhR binding affinity

• low toxicity and poor induction of CYP1A1

• exhibits partial AhR antagonist activity (for toxic responses)

• but elicits high antiestrogenic activity in • MCF-7 cells/rat uterus (agonist activity)

6-MCDF

O

Cl

CH3

Cl

Cl

PROPERTIES OF ALKYL PCDFs - 6-MCDF*

PROPERTIES OF ALKYL PCDFs - 6-MCDF*

* Selective AhR modulator (SAhRM)

SAhRMs FOR BREAST CANCER THERAPY

SAhRMs FOR BREAST CANCER THERAPY

• MCDF alone or plus tamoxifen are highly effective against ER+ breast cancer

(Cancer Res 61, 3902, 2001)

• MCDF inhibits ER- breast cancer cell and tumor growth

(Endocr Rel. Cancer 16, 835, 2009)

• Inhibition by MCDF not related to altered kinases, apoptosis or cell cycle genes

• Do SAhRMs such as MCDF work through miRs ?

INDUCTION/REPRESSION OF MiRs BY TCDD/MCDF

INDUCTION/REPRESSION OF MiRs BY TCDD/MCDF

Repressed MiRs Induced MiRs

Let-7d miR-134 miR-198 miR-373

miR-126 miR-205 miR-335

• Low expression of miR-335 in breast cancer predicts poor metastasis-free survival.

• Knockdown of miR-335 enhances MDA-MB-231 metastasis whereas overexpression of miR-335 blocks metastasis

• miR-335 suppresses expression of “prometastatic” genes such as SOX-4

INDUCTION OF POTENTIAL TUMOR SUPPRESSOR MiRs BY TCDD/MCDF –MiR-335*

INDUCTION OF POTENTIAL TUMOR SUPPRESSOR MiRs BY TCDD/MCDF –MiR-335*

* Massague et al Nature. 451, 177, 2007

TCDD/MCDF INDUCE MiR-335 IN MDA-MB-231 CELLS - AHR-DEPENDENT

TCDD/MCDF INDUCE MiR-335 IN MDA-MB-231 CELLS - AHR-DEPENDENT

DMSO TCDD MCDF0

1

2

3

4

5

iCT iAHR

Fo

ld In

du

cti

on

miR-335 AhRActin

iCT iAhRMDA-MB-231

0 hr 12 hr 24 hr0

0.5

1

1.5

2

2.5

3

3.5

4

4.5TCDD

MCDF

Fo

ld In

du

cti

on

miR-335MDA-MB-231

TCDD AND MCDF INHIBIT BREAST CANCER CELL MIGRATION AND INVASION-BOYDEN CHAMBER ASSAY

TCDD AND MCDF INHIBIT BREAST CANCER CELL MIGRATION AND INVASION-BOYDEN CHAMBER ASSAY

Upper Chamber

Lower Chamber

Membrane

Pores Migrated Cells

Cells

0

20

40

60

80

100

120

% C

on

tro

lCTL

MCDF(uM)

5 10

MDA-MB-231/24hr

**

MIR-335 ALSO INDUCES CELL INVASION BUT THIS RESPONSE IS AHR-INDEPENDENT

MIR-335 ALSO INDUCES CELL INVASION BUT THIS RESPONSE IS AHR-INDEPENDENT

CTL miR3350

20

40

60

80

100

120

iCTL

iAhR

iCTL+CTL iCTL+miR335

iAhR+miR335iAhR+CTL

% c

on

tro

l

Invasion Assay/MDA-MB-231

* *

TCDD/MCDF DECREASE MIR-335-REGULATED SOX4 IN MDA-MB-231 CELLS

TCDD/MCDF DECREASE MIR-335-REGULATED SOX4 IN MDA-MB-231 CELLS

iCTL iAhR0

0.2

0.4

0.6

0.8

1

1.2DMSO MCDF

*

Series10

0.2

0.4

0.6

0.8

1

1.2

1.4

DMSO TCDD

iCTL iAhR

*

SO

X4

mR

NA

(R

el.

DM

SO

)

SO

X4

mR

NA

(R

el.

DM

SO

)

TCDD/MCDF DECREASE SOX4 PROTEIN IN MDA-MBA-231 CELLS

TCDD/MCDF DECREASE SOX4 PROTEIN IN MDA-MBA-231 CELLS

SOX4

MDA-MB-231

DMSO

TCDD 10 nM

MCDF 5 nM

iAhR + + ++ +

+ +

+ +

- - -- - - -

- - - -

- - - -

β-Actin

MCDF INHIBITS MDA-MB-231 CELL LUNG METASTASIS IN MICE

MCDF INHIBITS MDA-MB-231 CELL LUNG METASTASIS IN MICE

Corn Oil (CTL)

MCDF (40 mg/kg/d)

1 2 30

20

40

60

80

No

. o

f c

olo

nie

s

No. of colonies

No cellsCO MCDF+T

+T

ND

ANTIMETASTATIC ACTIVITY OF AHR AGONISTS IN ER BREAST CANCER

ANTIMETASTATIC ACTIVITY OF AHR AGONISTS IN ER BREAST CANCER

Normal cells Preneoplastic cells

Cancer cells(Invasive carcinoma)

Metastasis

SOX4

SOX4 and other miR-335 regulated proteins

miR-335

miR-335

SOX4

SOX4 and other miR-335 regulated metastatic

mRNAs

arntAhRLigand activated Ahr

REFERENCESREFERENCES

1.Brase, J. C., Wuttig, D., Kuner, R. and Sultmann, H. Serum microRNAs as non-invasive biomarkers for cancer. Mol Cancer 9:306, 2010.2.Giovannetti, E., Funel, N., Peters, G. J., Del Chiaro, M., Erozenci, L. A., Vasile, E., Leon, L. G., Pollina, L. E., Groen, A., Falcone, A., Danesi, R., Campani, D., Verheul, H. M. and Boggi, U. MicroRNA-21 in pancreatic cancer: correlation with clinical outcome and pharmacologic aspects underlying its role in the modulation of gemcitabine activity. Cancer Res 70:4528-38, 2010.3.Gui, J., Tian, Y., Wen, X., Zhang, W., Zhang, P., Gao, J., Run, W., Tian, L., Jia, X. and Gao, Y. Serum microRNA characterization identifies miR-885-5p as a potential marker for detecting liver pathologies. Clin Sci (Lond) 120:183-93, 2011.4.Hatley, M. E., Patrick, D. M., Garcia, M. R., Richardson, J. A., Bassel-Duby, R., van Rooij, E. and Olson, E. N. Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21. Cancer Cell 18:282-93, 2010.5.Huang, S. and He, X. The role of microRNAs in liver cancer progression. Br J Cancer 104:235-40, 2011.6.Hwang, J. H., Voortman, J., Giovannetti, E., Steinberg, S. M., Leon, L. G., Kim, Y. T., Funel, N., Park, J. K., Kim, M. A., Kang, G. H., Kim, S. W., Del Chiaro, M., Peters, G. J. and Giaccone, G. Identification of microRNA-21 as a biomarker for chemoresistance and clinical outcome following adjuvant therapy in resectable pancreatic cancer. PLoS One 5:e10630, 2010.7.Kim, K., Chadalapaka, G., Lee, S. O., Yamada, D., Sastre-Garau, X., Defossez, P. A., Park, Y. Y., Lee, J. S. and Safe, S. Identification of oncogenic microRNA-17-92/ZBTB4/specificity protein axis in breast cancer. Oncogene 2011.8.Ma, X., Kumar, M., Choudhury, S. N., Becker Buscaglia, L. E., Barker, J. R., Kanakamedala, K., Liu, M. F. and Li, Y. Loss of the miR-21 allele elevates the expression of its target genes and reduces tumorigenesis. Proc Natl Acad Sci U S A 108:10144-9, 2011.

REFERENCESREFERENCES

9.McDougal, A., Wormke, M., Calvin, J. and Safe, S. Tamoxifen-induced antitumorigenic/antiestrogenic action synergized by a selective aryl hydrocarbon receptor modulator. Cancer Res 61:3902-7, 2001.10.Medina, P. P., Nolde, M. and Slack, F. J. OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature 467:86-90, 2010.11.Mertens-Talcott, S. U., Chintharlapalli, S., Li, X. and Safe, S. The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells. Cancer Res 67:11001-11, 2007.12.Szymanski, M. and Barciszewski, J. Beyond the proteome: non-coding regulatory RNAs. Genome Biol 3:reviews0005, 2002.13.Ueda, T., Volinia, S., Okumura, H., Shimizu, M., Taccioli, C., Rossi, S., Alder, H., Liu, C. G., Oue, N., Yasui, W., Yoshida, K., Sasaki, H., Nomura, S., Seto, Y., Kaminishi, M., Calin, G. A. and Croce, C. M. Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis. Lancet Oncol 11:136-46, 2010.14.Wu, S., Huang, S., Ding, J., Zhao, Y., Liang, L., Liu, T., Zhan, R. and He, X. Multiple microRNAs modulate p21Cip1/Waf1 expression by directly targeting its 3' untranslated region. Oncogene 29:2302-8, 2010.15.Zhang, S., Kim, K., Jin, U. H., Pfent, C., Cao, H., Amendt, B., Liu, X., Wilson-Robles, H. and Safe, S. Aryl hydrocarbon receptor (AHR) agonists induce microRNA-335 expression and inhibit lung metastasis of estrogen receptor negative breast cancer cells. Mol Cancer Therap. 11, 108-118, 2012.16.Zhang, S., Lei, P., Liu, X., Li, X., Walker, K., Kotha, L., Rowlands, C. and Safe, S. The aryl hydrocarbon receptor as a target for estrogen receptor-negative breast cancer chemotherapy. Endocr Relat Cancer 16:835-44, 2009.

SHINING A LIGHT ON THE GENOME’S ‘DARK MATTER’ NON-CODING RNAs (nc RNAs) : MICRORNAs AND CANCER...

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Transcript of SHINING A LIGHT ON THE GENOME’S ‘DARK MATTER’ NON-CODING RNAs (nc RNAs) : MICRORNAs AND CANCER...