Research team Weng-Onn Lui
Small RNAs in cancer development
Our group is mainly focusing on the role of small RNAs in cancer development and drug resistance. Small RNA, particularly microRNA (miRNA), plays an important role in regulating gene expression at post-transcriptional level. Altered expression of specific small RNAs can cause diseases. Study of small RNA expression and function in cancer cells could contribute to greater understanding of how small RNAs are involved in cancer development and drug resistance, which may lead to identification of important diagnostic/ prognostic markers for clinical practice, as well as potential target molecules for development of targeted cancer treatment.
A major effort of our previous work had focused on the identification of novel small RNAs, the documentation of miRNA expression patterns in several cancer types, and evaluation of their potential use in tumor classification and prognostication. Our current work primarily focuses on the functional roles of small RNAs along with other regulatory components in clinically relevant experimental systems. Several ongoing projects are briefly described below:
Molecular pathogenesis of Merkel cell carcinoma
Merkel cell carcinoma (MCC) is an aggressive and lethal type of skin cancer, which is frequently infected by Merkel cell polyomavirus (MCPyV). However the molecular mechanism by which the virus induces tumorigenesis remains unclear. We recently identify specific miRNAs associated with MCPyV status, tumor metastasis and disease-specific survival in MCC patients, suggesting the importance of miRNAs in MCC development and progression. In this project, we aim to understand the functional roles of viral oncoproteins and miRNAs in MCC, and to identify biomarkers related to MCC development and progression.
Role and mechanism of microRNA regulation in drug resistance
Many human cancers are commonly initiated by activating mutations in kinases, which contribute to cancer development. This has prompted to the development of kinase inhibitors for blocking the oncogenic process. These small molecule inhibitors bind and inhibit kinase activity of specific kinases. Although kinase inhibitors have been used as specific targeted therapy for selected malignancies and have markedly improved patient outcomes, development of acquired kinase inhibitor resistance remains a major clinical challenge. Identifying the mechanisms of kinase inhibitor resistance is warranted to improve the effectiveness of these therapies and patient outcome. The aim of this project is to investigate the role of miRNAs in acquired BRAF inhibitor and imatinib resistance.
Molecular mechanisms of germ cell development and tumorigenesis
The objective of this work is to better understand the molecular mechanisms regulating germ cell development and tumor formation. We hypothesize that the PIWI proteins (germline-specific Argonaute proteins), small RNAs (including piwi-interacting RNAs and microRNAs), and subcellular localization of c-KIT are necessary for the maintenance of germ cell function. Misregulation of these proteins and small RNAs during germ cell development can lead to germ cell dysfunction and tumorigenesis. Our ongoing work is to: (i) elucidate the biological functions of specific microRNAs in germ cell viability and in testicular germ cell tumor; (ii) investigate piRNA expression and mechanisms in testicular germ cell tumors; (iii) define the role of human PIWI homologs in germ cell development and tumorigenesis; and (iv) unwrap the functional role of paranuclear KIT in testicular germ cell tumors.
Role of RNA interference components in the nucleus of cancer cells
Double stranded RNA can regulate gene expression through small RNA molecules generated by Dicer. These small RNAs are loaded into a protein complex to mediate gene silencing by targeting specific mRNA in the cytoplasm. This process, called RNA interference (RNAi), were thought to occur only in the cytoplasm; however emerging data support that RNAi may occur in the nucleus of human cells. We previously showed that miRNA machinery factors were overexpressed in several cancer types. Interestingly, we noted that Dicer and TARBP2 were localized in both cytoplasm and nucleus of cancer cells, while both proteins were mainly found in the cytoplasm of non-malignant cells. The objective of this work is to explore the roles of RNAi pathway proteins in the nucleus of human cancer cells.
Cancer Center Karolinska R8:04,
Karolinska University Hospital-Solna,
SE-171 76 Stockholm, Sweden
Phone: +46-8 5177 3930 or +46 8 5177 3616
Weng-Onn Lui, PhD, Associate professor (Docent and Lektor in Molecular Cancer Genetics), Team leader
Roger Chang, MSc, PhD student
Satendra Kumar, MSc, PhD student
Wen-Kuan Huang, MD, PhD student
Hao Shi, MSc, PhD student
Patrick Scicluna, MSc, PhD student
Previous team members
Stefano Caramuta (2012), Postdoc at KI
Hong Xie (2014), Senior Lecturer at Tianjin Medical University, China
Pinar Akcakaya (2015), Postdoc at AstraZeneca, Göteborg
Deniz Özata (2015), Postdoc at U Mass Medical School, USA (Phil Zamore's lab)
Postdoctoral fellows/visiting researchers
Lin-Kiat Lee (PhD, University of Malaya)
Praveensingh Hajeri, KI-University of Minnesota Partnership: Frontiers in Biomedical Research Scholar Award
Katarina Zeljic (Associate Professor, University of Belgrade, Serbia)
MSc students at KI: Amani Al-Khalfi, Iryna Kolosenko (2009), Ferdous Rahman (2010), Jason Serviss (2013)
MSc students at other institutions: Vijay Joshua Balasingh (KTH, 2010), Ram P. Yadav (Uppsala University, 2010), Patrick Scicluna (Lund University, 2011), Roger Chang (Stockholm University, 2012), Ditte Rigardt (Stockholm University 2013)
BSc students: Mahmut Deniz Özata (Izmir Institute of Technology, Turkey; Jun-Sep 2009), Anastasia Gangaev (Johannes Gutenberg University Mainz; May-Jul 2014), Ewa Dzwonkowska (Poznan University of Life Sciences, Poland; 2015), Beatriz Garcia Majano (University of Castilla-la Mancha, Toledo, Spain; 2016), Agata Bąk (Warsaw University, Poland; 2016)
The present research is generously supported by grants from:
- The Swedish Research Council
- The Swedish Cancer Society
- The Cancer Research Foundations of Radiumhemmet
- Karolinska Institutet
- Stockholm County Council