Antitumor effect of SIRT1 inhibition in human HCC tumor models in vitro and in vivo

Portmann, Simone; Fahrner, René; Lechleiter, Antje; Keogh, Adrian; Overney, Sarah; Lämmle, Alexander; Mikami, Kei; Montani, Matteo; Tschan, Mario; Candinas, Daniel; Keogh-Stroka, Deborah M. (2013). Antitumor effect of SIRT1 inhibition in human HCC tumor models in vitro and in vivo. Molecular cancer therapeutics, 12(4), pp. 499-508. American Association for Cancer Research AACR 10.1158/1535-7163.MCT-12-0700

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Sirtuins (SIRT1-7) are a highly conserved family of NAD(+)-dependent enzymes that control the activity of histone and nonhistone regulatory proteins. SIRT1 is purposed to promote longevity and to suppress the initiation of some cancers. Nevertheless, SIRT1 is reported to function as a tumor suppressor as well as an oncogenic protein. Our data show that compared with normal liver or surrounding tumor tissue, SIRT1 is strongly overexpressed in human hepatocellular carcinoma (HCC). In addition, human HCC cell lines (Hep3B, HepG2, HuH7, HLE, HLF, HepKK1, skHep1) were screened for the expression of the sirtuin family members and only SIRT1 was consistently overexpressed compared with normal hepatocytes. To determine its effect on HCC growth, SIRT1 activity was inhibited either with lentiviruses expressing short hairpin RNAs or with the small molecule inhibitor, cambinol. Knockdown or inhibition of SIRT1 activity had a cytostatic effect, characterized by an altered morphology, impaired proliferation, an increased expression of differentiation markers, and cellular senescence. In an orthotopic xenograft model, knockdown of SIRT1 resulted in 50% fewer animals developing tumors and cambinol treatment resulted in an overall lower tumor burden. Taken together, our data show that inhibition of SIRT1 in HCC cells impairs their proliferation in vitro and tumor formation in vivo. These data suggest that SIRT1 expression positively influences the growth of HCC and support further studies aimed to block its activity alone or in combination as a novel treatment strategy.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie

04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Portmann, Simone; Fahrner, René; Lechleiter, Antje; Keogh, Adrian; Overney, Sarah; Lämmle, Alexander; Mikami, Kei; Montani, Matteo; Tschan, Mario; Candinas, Daniel and Keogh-Stroka, Deborah M.

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

1535-7163

Publisher:

American Association for Cancer Research AACR

Language:

English

Submitter:

Andrea Arnold

Date Deposited:

03 Apr 2014 15:08

Last Modified:

03 Apr 2014 15:08

Publisher DOI:

10.1158/1535-7163.MCT-12-0700

PubMed ID:

23339189

URI:

https://boris.unibe.ch/id/eprint/46324

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