RUNX2/miR-31/SATB2 pathway in nickel-induced BEAS-2B cell transformation

Nickel (Ni) compounds are classified as Group 1 carcinogens by the International Agency for Research on Cancer (IARC) and are known to be carcinogenic to the lungs. In our previous study, special AT-rich sequence-binding protein 2 (SATB2) was required for Ni-induced BEAS-2B cell transformation. In the present study, a pathway that regulates the expression of SATB2 protein was investigated in Ni-transformed BEAS-2B cells using western blotting and RT-qPCR for expression, and soft agar, migration and invasion assays for cell transformation. Runt-related transcription factor 2 (RUNX2), a master regulator of osteogenesis and an oncogene, was identified as an upstream regulator for SATB2. Ni induced RUNX2 expression and initiated BEAS-2B transformation and metastatic potential. Previously, miRNA-31 was identified as a negative regulator of SATB2 during arsenic-induced cell transformation, and in the present study it was identified as a downstream target of RUNX2 during carcinogenesis. miR-31 expression was reduced in Ni-transformed BEAS-2B cells, which was required to maintain cancer hallmarks. The expression level of miR-31 was suppressed by RUNX2 in BEAS-2B cells, and this increased the expression level of SATB2, initiating cell transformation. Ni caused the repression of miR-31 by placing repressive marks at its promoter, which in turn increased the expression level of SATB2, leading to cell transformation.