Metallothionein-3: Potential therapeutic target for sorafenib resistance in hepatocellular carcinoma

abstract

English

Background:Metallothionein-3 (M-3) has poorly characterized functions in hepato-cellular carcinoma (HCC). HCC is a significant health problem. Globally is the second most common cause of cancer-associated death. Sorafenib was originally identified asan inhibitor of multiple oncogenic kinases and remains the only approved systemictherapy for advanced HCC. However, acquired resistance to sorafenib has been foundin HCC patients, which results in poor prognosis. Overexpression of MT-3 decreasedthe sensitivity of HCC cells to sorefenib. Here, we investigated the impact of MT-3 up-regulation in HCC cells and the mechanisms underlying the sorafenib-resistance. Methods:To increase the expression of MT-3 HCC cells were transiently transfectedwith a plasmid containing MT-3 gene or with empty vector. The cDNA microarrayswere accomplished using the ElectraSenseTM Reader. MS analysis was performedusing a Q-Exactive MS. We used chick chorioallantoic membrane assay as in vivomodel. Results:A cDNA profiling revealed that sorafenib resistance has a specific tran-scriptomic signature involving genes responsible for ion transport, trafficking and DNArepair. Also, The MS analysis data strongly suggest that resistance HCC cells acquired acomplex regulatory network that significantly affects the ability of HCC cells toremove the ROS and activation of glycolysis. We provide thefirst evidence that up-regulation of MT3 resulted in increased dissociation, invasion, and intravasation fromthe primary tumours to the veins. In addition, MT3 profoundly impacted bloodmigration of Nbl cells and their extravasation to chicken organs. Conclusion:From a perspective of future utilization of our data, we anticipate thatseveral identified genes and proteins could serve as prognostic biomarkers ofoutcome of sorafenib therapy. The increased expression of MT-3 within tumour massshould inform about worse prognosis and also decreased efficiency of sorafenib-based chemotherapy in HCC.

Metallothionein-3; Hepatocellular carcinoma (HCC); sorafenib

MERLOS RODRIGO, M.; MICHÁLKOVÁ, H.; ŠMÍDOVÁ, V.; CASAR, B.; DE LOS RIOS, V.; CASAL ÁLVAREZ, J.; MACIA, M.S.; RAMOS, D.F.; CHANTAR, M.L.M.; ADAM, V.; HEGER, Z.

31. 7. 2021

0923-7534

ANNALS OF ONCOLOGY

32

MO38-2

United Kingdom of Great Britain and Northern Ireland

S323

S323

1

https://www.sciencedirect.com/science/article/pii/S0923753421018603?via%3Dihub