Īnoikis is a type of apoptosis activated upon cell detachment from the extracellular matrix (ECM), and normal epithelial cells usually undergo anoikis when they become detached from the ECM. Once cancer cells enter the bloodstream, these circulating tumor cells can overcome various adversities, such as shear stress and anoikis, resulting in their survival.
MINDLY RETARDED GOAT SERIES
Tumor metastasis involves various series of sequential steps, such as dissociation of cancer cells from primary tumor invasion of cancer cells into the extracellular matrix (ECM) intravasation of cancer cells into the circulation system cell survival during circulation, extravasation, and adaptation of cancer cells to a new environment to settle down in the secondary site and proliferation in new microenvironments to form secondary tumors. Tumor metastasis is responsible for more than 90% of cancer-related deaths. Our study suggests FAM188B as a potential target for controlling tumor malignancy. Taken together, these findings indicate that FAM188B plays an important role in anoikis resistance and metastatic characteristics by maintaining the levels of various oncogenic proteins and/or their activity, leading to tumor malignancy. Finally, tail vein injection of si-FAM188B-treated A549 cells resulted in a decrease in lung metastasis and an increase in mice survival in vivo. Moreover, FAM188B downregulation reduced metastatic characteristics, such as cell adhesion, invasion, and migration, as well as growth in 3D culture conditions. In addition, cells transfected with si-FAM188B had decreased expression of FOXM1, an oncogenic transcription factor involved in cell growth and survival.
Intriguingly, si-FAM188B treatment increased EGFR mRNA levels but decreased its protein levels, which was reversed by treatment with the proteasomal inhibitor MG132, indicating that FAM188B regulates EGFR levels via the proteasomal pathway. FAM188B knockdown decreased the activities of several oncogenic proteins downstream of EGFR that are involved in anoikis resistance, including pAkt, pSrc, and pSTAT3, with little changes to their protein levels. FAM188B knockdown resulted in EGFR downregulation and thus decreased its activity. FAM188B knockdown using si-FAM188B inhibited the growth of all three human lung cancer cell lines cultured in both attachment and suspension conditions. In this study, we demonstrated that FAM188B knockdown sensitized anoikis of lung cancer cell lines expressing WT-EGFR (A549 and H1299) or TKI-resistant EGFR mutant T790M/L858R (H1975).
Although family with sequence similarity 188 member B (FAM188B) is predicted as a new deubiquitinase (DUB) member, its biological function has not been fully studied.
Although the sensitization of cancer cells to anoikis is a potential strategy to prevent metastasis, the mechanism underlying anoikis resistance is not well defined.
Acquisition of anoikis resistance is critical for cancer cells to survive during circulation and, thus, metastasize at a secondary site. Anoikis is a type of apoptosis induced by cell detachment from the extracellular matrix (ECM), which removes mislocalized cells.
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