New insights into Colorectal Cancer progression
24 Aug 2015
SPINK1 promotes Colorectal Cancer progression by down regulating Metallothioneins expression
Dr Bushra Ateeq, Intermediate Fellow, IIT Kanpur
Colorectal cancer (CRC) is the third most commonly diagnosed cancer type; approximately one million individuals worldwide are diagnosed with the disease each year. Anti-epidermal growth factor receptor (EGFR) therapies such as monoclonal antibody (cetuximab) against EGFR are either administered as part of first-line treatment or as a final option when other treatments fail. However, half of the CRC patients who harbor mutations in KRAS, NRAS, and BRAF genes acquire resistance to anti-EGFR drugs, thus highlighting the necessity for additional targeted therapies. In the current study, we have shown that SPINK1 (Serine Protease Inhibitor Kazal type 1) is highly expressed among CRC patients and demonstrated the functional significance of SPINK1 in disease progression and metastases. SPINK1 over-expression in CRC has been associated with advanced stage of the disease, poor clinical outcome and metastasis to liver.
We have shown that silencing SPINK1 in BRAF mutation positive WiDr colon adenocarcinoma cells demonstrate decrease in cell proliferation, invasion, soft agar colony formation and reduced tumor growth and distant metastases in in-vivo model systems. Importantly, SPINK1 silencing led to up-regulation of various metallothionein isoforms, considered as tumor suppressors in CRC, which confers sensitivity to chemotherapeutic drug doxorubicin. Taken together, our findings strengthen the rationale for using the combinatorial treatment approach for the SPINK1-positive CRC patients. Our study also demonstrates an important role for the SPINK1 over-expression in CRC disease progression, a phenomenon that needs careful evaluation towards effective therapeutic target development.
Reference: Oncogenesis (2015) 4, e162; doi:10.1038/oncsis.2015.23
Full text available on: https://www.nature.com/oncsis/journal/v4/n8/full/oncsis201523a.html