In summary, this study identified V-ATPase as a targetable protein vital for anoikis resistance based on objective screening by global profile gene expression alterations in forced suspension culture and elucidated STAT3 as a key regulator of V-ATPase expression in anchorage-independent cells; thus enhance tumor cells to be anoikis resistant due to impaired ROS production. Here, STAT3 is linked to neoplasm.