Abstract 501: A RET-related microRNA, miR-153-3p, acts as a tumor suppressor in medullary thyroid carcinoma (MTC) via S6K signaling

Background Medullary thyroid carcinoma (MTC), which comprises 3-5% of all thyroid cancers, originates from a small population of neuroendocrine calcitonin C-cells of thyroid gland. Gain-of-function mutations of the human Rearranged during Transfection (RET) proto-oncogene have been recognized as the...

Full description

Saved in:
Bibliographic Details
Published inCancer research (Chicago, Ill.) Vol. 78; no. 13_Supplement; p. 501
Main Authors Joo, Lauren Jin Suk, Weiss, Jocelyn, Gill, Anthony J., Clifton-Bligh, Roderick, Brahmbhatt, Himanshu, MacDiarmid, Jennifer A., Gild, Matti L., Robinson, Bruce G., Sidhu, Stan B., Zhao, Jing Ting
Format Journal Article
LanguageEnglish
Published 01.07.2018
Online AccessGet full text

Cover

Loading…
Abstract Background Medullary thyroid carcinoma (MTC), which comprises 3-5% of all thyroid cancers, originates from a small population of neuroendocrine calcitonin C-cells of thyroid gland. Gain-of-function mutations of the human Rearranged during Transfection (RET) proto-oncogene have been recognized as the key driver of MTC tumorigenesis. RET has been targeted by tyrosine kinase inhibitors (TKIs), however with modest efficacy. Many of the microRNAs (miRNAs) identified in human genome have been associated with cancer and have prompted interest in the establishment of miRNA-based therapeutics. However miRNA studies in MTC has been hampered due to the lack of normal C-cell tissue as a differential expression comparator. Aims We aimed to characterize differentially expressed miRNAs, which play fundamental roles in MTC tumorigenesis and in modulation of TKI responses. Methods RET of human MTC cells were silenced using TKI, Cabozantinib, or siRNA. Small RNA sequencing was performed (AGRF) to identify differentially expressed miRNAs before and after RET inhibition. MiRNA effects on cell proliferation (MTS assay), cell cycle and apoptosis (flow cytometry, Western blot) were investigated with gain-of-function studies. For in vivo study, MTC xenografts were established and miRNAs were intravenously delivered using nanoparticle delivery vehicles invented by biotechnology company - EnGeneIC Ltd. Results miR-153-3p was identified to be under-expressed in MTC following RET inhibition. Restoration of miR-153-3p significantly reduced cell proliferation, induced G2 cell arrest and increased cell apoptosis. Furthermore, combined treatment of miR-153-3p and Cabozantinib caused greater cell proliferation inhibition compared to individual treatment. miR-153-3p targets ribosomal protein S6 kinase B1 (RPS6KB1) and reduced phosphorylation of Bcl-2 associated death promoter (BAD) protein. In vivo delivery of miR-153-3p significantly impeded tumor growth compared to scrambled sequence. Combination of miR-153-3p delivery and oral administration of Cabozantinib resulted in further tumor stabilization effect. Conclusion miR-153-3p reveals a significant tumor suppressive role in MTC via S6K signaling, demonstrating its important therapeutic potential for MTC patients. Citation Format: Lauren Jin Suk Joo, Jocelyn Weiss, Anthony J. Gill, Roderick Clifton-Bligh, Himanshu Brahmbhatt, Jennifer A. MacDiarmid, Matti L. Gild, Bruce G. Robinson, Stan B. Sidhu, Jing Ting Zhao. A RET-related microRNA, miR-153-3p, acts as a tumor suppressor in medullary thyroid carcinoma (MTC) via S6K signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 501.
AbstractList Background Medullary thyroid carcinoma (MTC), which comprises 3-5% of all thyroid cancers, originates from a small population of neuroendocrine calcitonin C-cells of thyroid gland. Gain-of-function mutations of the human Rearranged during Transfection (RET) proto-oncogene have been recognized as the key driver of MTC tumorigenesis. RET has been targeted by tyrosine kinase inhibitors (TKIs), however with modest efficacy. Many of the microRNAs (miRNAs) identified in human genome have been associated with cancer and have prompted interest in the establishment of miRNA-based therapeutics. However miRNA studies in MTC has been hampered due to the lack of normal C-cell tissue as a differential expression comparator. Aims We aimed to characterize differentially expressed miRNAs, which play fundamental roles in MTC tumorigenesis and in modulation of TKI responses. Methods RET of human MTC cells were silenced using TKI, Cabozantinib, or siRNA. Small RNA sequencing was performed (AGRF) to identify differentially expressed miRNAs before and after RET inhibition. MiRNA effects on cell proliferation (MTS assay), cell cycle and apoptosis (flow cytometry, Western blot) were investigated with gain-of-function studies. For in vivo study, MTC xenografts were established and miRNAs were intravenously delivered using nanoparticle delivery vehicles invented by biotechnology company - EnGeneIC Ltd. Results miR-153-3p was identified to be under-expressed in MTC following RET inhibition. Restoration of miR-153-3p significantly reduced cell proliferation, induced G2 cell arrest and increased cell apoptosis. Furthermore, combined treatment of miR-153-3p and Cabozantinib caused greater cell proliferation inhibition compared to individual treatment. miR-153-3p targets ribosomal protein S6 kinase B1 (RPS6KB1) and reduced phosphorylation of Bcl-2 associated death promoter (BAD) protein. In vivo delivery of miR-153-3p significantly impeded tumor growth compared to scrambled sequence. Combination of miR-153-3p delivery and oral administration of Cabozantinib resulted in further tumor stabilization effect. Conclusion miR-153-3p reveals a significant tumor suppressive role in MTC via S6K signaling, demonstrating its important therapeutic potential for MTC patients. Citation Format: Lauren Jin Suk Joo, Jocelyn Weiss, Anthony J. Gill, Roderick Clifton-Bligh, Himanshu Brahmbhatt, Jennifer A. MacDiarmid, Matti L. Gild, Bruce G. Robinson, Stan B. Sidhu, Jing Ting Zhao. A RET-related microRNA, miR-153-3p, acts as a tumor suppressor in medullary thyroid carcinoma (MTC) via S6K signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 501.
Author Clifton-Bligh, Roderick
Weiss, Jocelyn
Sidhu, Stan B.
Zhao, Jing Ting
Gill, Anthony J.
Brahmbhatt, Himanshu
Robinson, Bruce G.
Gild, Matti L.
MacDiarmid, Jennifer A.
Joo, Lauren Jin Suk
Author_xml – sequence: 1
  givenname: Lauren Jin Suk
  surname: Joo
  fullname: Joo, Lauren Jin Suk
– sequence: 2
  givenname: Jocelyn
  surname: Weiss
  fullname: Weiss, Jocelyn
– sequence: 3
  givenname: Anthony J.
  surname: Gill
  fullname: Gill, Anthony J.
– sequence: 4
  givenname: Roderick
  surname: Clifton-Bligh
  fullname: Clifton-Bligh, Roderick
– sequence: 5
  givenname: Himanshu
  surname: Brahmbhatt
  fullname: Brahmbhatt, Himanshu
– sequence: 6
  givenname: Jennifer A.
  surname: MacDiarmid
  fullname: MacDiarmid, Jennifer A.
– sequence: 7
  givenname: Matti L.
  surname: Gild
  fullname: Gild, Matti L.
– sequence: 8
  givenname: Bruce G.
  surname: Robinson
  fullname: Robinson, Bruce G.
– sequence: 9
  givenname: Stan B.
  surname: Sidhu
  fullname: Sidhu, Stan B.
– sequence: 10
  givenname: Jing Ting
  surname: Zhao
  fullname: Zhao, Jing Ting
BookMark eNo9kNtKAzEQhoNUsK2-gRdzqWBqsrvZg3dLqQdsFereL7ObpEb2RLIVeu2Lm1IRBubA_w8z34xMur5ThFxztuBcpPdchClNokgs8k3AeEoF42dk-j-ekCljzI-jJLggM-e-fCs4E1Pyk1dutFiP4D0PkMN2VVCrGhyVhNbUtt--5Xe-2lK_jobDHXixA_QB477tLbj9MFjlnC9NB62S-6ZBe4Dx82B7I6FGW5uubxFuNsXyFr4Nwkf8Cs7sOmxMt7sk5xobp67-8pwUj6ti-UzX708vy3xN6yzmNGYq4FmMQmRBKpFpyVlaYVzFgfYCiWGVsSBE5FKjRBEkumaJ1NpbuEricE6i01r_lHNW6XKwpvWXlpyVR47lEVh5BFaeOJaeSfgLaxJmpg
CitedBy_id crossref_primary_10_1016_j_biopha_2019_108654
crossref_primary_10_1186_s40659_018_0203_6
ContentType Journal Article
DBID AAYXX
CITATION
DOI 10.1158/1538-7445.AM2018-501
DatabaseName CrossRef
DatabaseTitle CrossRef
DatabaseTitleList CrossRef
DeliveryMethod fulltext_linktorsrc
Discipline Medicine
EISSN 1538-7445
EndPage 501
ExternalDocumentID 10_1158_1538_7445_AM2018_501
GroupedDBID ---
-ET
18M
29B
2WC
34G
39C
476
53G
5GY
5RE
5VS
6J9
AAYXX
ABOCM
ACGFO
ACIWK
ACPRK
ACSVP
ADBBV
ADCOW
ADNWM
AENEX
AFHIN
AFOSN
AFRAH
ALMA_UNASSIGNED_HOLDINGS
BAWUL
BTFSW
CITATION
CS3
DIK
DU5
EBS
EJD
F5P
FRP
GX1
H13
IH2
KQ8
L7B
LSO
OK1
P0W
P2P
PQQKQ
RCR
RHF
RHI
RNS
SJN
TR2
W2D
W8F
WH7
WOQ
YKV
YZZ
ID FETCH-LOGICAL-c961-60e2196a55928da0fd108ba6b62fc96da3b9023aa1dfada527fc07dff6a51e763
ISSN 0008-5472
IngestDate Thu Nov 21 23:16:56 EST 2024
IsPeerReviewed true
IsScholarly true
Issue 13_Supplement
Language English
LinkModel OpenURL
MergedId FETCHMERGED-LOGICAL-c961-60e2196a55928da0fd108ba6b62fc96da3b9023aa1dfada527fc07dff6a51e763
PageCount 1
ParticipantIDs crossref_primary_10_1158_1538_7445_AM2018_501
PublicationCentury 2000
PublicationDate 2018-07-01
PublicationDateYYYYMMDD 2018-07-01
PublicationDate_xml – month: 07
  year: 2018
  text: 2018-07-01
  day: 01
PublicationDecade 2010
PublicationTitle Cancer research (Chicago, Ill.)
PublicationYear 2018
SSID ssj0005105
Score 2.3118281
Snippet Background Medullary thyroid carcinoma (MTC), which comprises 3-5% of all thyroid cancers, originates from a small population of neuroendocrine calcitonin...
SourceID crossref
SourceType Aggregation Database
StartPage 501
Title Abstract 501: A RET-related microRNA, miR-153-3p, acts as a tumor suppressor in medullary thyroid carcinoma (MTC) via S6K signaling
Volume 78
hasFullText 1
inHoldings 1
isFullTextHit
isPrint
link http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV1da9swFBWhg7GXsU_20Q097GHDVRYnli3vzSvdSkoKSzPWNyPbEjM4dkmTwva6H7y_sHtlWTZbGevAmMTYN4rvQbqSzj2XkFeBLmbKjyWDCXLAgjybskyEivGwQHkllEQ3ap-n4fHnYH7Oz0ejnwPW0m6bjfPv1-aV_I9X4Rr4FbNkb-BZZxQuwGfwL5zBw3D-Jx8nGS5U5FuPT_w2xXx5tGImPQXiyDVy7ZanCb7Fdblk0OuwmSlHJ5HBIeHwtrt1s_EudxeGD2u46bjdDvNSZNOBEzdNWaB8dV7WzVpiPLpYHeJSwlUpvbPwxEMCiKy6AbDXPMjVxrNKQl_NVnHL-TB9UlWNBysQ86bpMrRV7c2hBWc7lz_0RZWXdqsiV9U3B-WPVobbih9487HbTalKjXWR31dlu3-0xHJvnfi_XeDwhSPD9p22YDxoK_yMVd9PR0GrRNl15JEYAnaWmrqoPYGo7aG5Na2G3_4cRzjmRrhfGScL0zL38FC2-7fh1JEczfSKixStpGglba2kHPMNb6FyIxZ7OPnUy9tzy7nt_rHN9QQrb69ryyCWGgRFq3vkrp3N0KSF5n0yUvUDcnth-RoPyY8OoRTsvKMJHeCTdvg8oD06Dyhik0o4qMEm7bFJy5o6bFKLTeqwSV8DMt9QwCUFXFKHy0dk9eFodXjMbNkPlsehz8KJglE0lDDVnYpCTnThT0QmwyycarihkLMshkBTSr_QspB8Gul8EhVawyO-guHyMdmrm1o9ITSLY1QU1EUu8kDEXERSSA0xv1ZK-nH0lLDu_aUXrbhL-jevPbvh_c_JnR7Q-2Rvu9mpFxDDbrOXxu-_ACw-kIk
link.rule.ids 314,780,784,27924,27925
linkProvider Colorado Alliance of Research Libraries
openUrl ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Abstract+501%3A+A+RET-related+microRNA%2C+miR-153-3p%2C+acts+as+a+tumor+suppressor+in+medullary+thyroid+carcinoma+%28MTC%29+via+S6K+signaling&rft.jtitle=Cancer+research+%28Chicago%2C+Ill.%29&rft.au=Joo%2C+Lauren+Jin+Suk&rft.au=Weiss%2C+Jocelyn&rft.au=Gill%2C+Anthony+J.&rft.au=Clifton-Bligh%2C+Roderick&rft.date=2018-07-01&rft.issn=0008-5472&rft.eissn=1538-7445&rft.volume=78&rft.issue=13_Supplement&rft.spage=501&rft.epage=501&rft_id=info:doi/10.1158%2F1538-7445.AM2018-501&rft.externalDBID=n%2Fa&rft.externalDocID=10_1158_1538_7445_AM2018_501
thumbnail_l http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0008-5472&client=summon
thumbnail_m http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0008-5472&client=summon
thumbnail_s http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0008-5472&client=summon