Potential Role of the Fragile Histidine Triad in Cancer Evo-Dev

SIMPLE SUMMARY: Tumor development follows an evolutionary pattern of “mutation-selection-adaptation”, characterized by exogenous oncogenic induction and endogenous replicative stress. The fragile histidine triad (FHIT) is a tumor suppressor. Aberrant transcription or reduction in the transcription and translation of the FHIT is an early event occurring in at least 50% of preneoplastic lesions and human cancers. Here, we summarized the evidence of the FHIT in cancers and evaluated the role of the FHIT in bridging macroevolution and microevolution and its functions in critical aspects of cancer evolutionary development (Cancer Evo-Dev), a theory developed to elucidate the mechanisms of non-resolving inflammation-induced carcinogenesis and develop suitable prophylactic and therapeutic options for malignant diseases. ABSTRACT: Cancer development follows an evolutionary pattern of “mutation-selection-adaptation” detailed by Cancer Evolution and Development (Cancer Evo-Dev), a theory that represents a process of accumulating somatic mutations due to the imbalance between the mutation-promoting force and the mutation-repairing force and retro-differentiation of the mutant cells to cancer initiation cells in a chronic inflammatory microenvironment. The fragile histidine triad (FHIT) gene is a tumor suppressor gene whose expression is often reduced or inactivated in precancerous lesions during chronic inflammation or virus-induced replicative stress. Here, we summarize evidence regarding the mechanisms by which the FHIT is inactivated in cancer, including the loss of heterozygosity and the promoter methylation, and characterizes the role of the FHIT in bridging macroevolution and microevolution and in facilitating retro-differentiation during cancer evolution and development. It is suggested that decreased FHIT expression is involved in several critical steps of Cancer Evo-Dev. Future research needs to focus on the role and mechanisms of the FHIT in promoting the transformation of pre-cancerous lesions into cancer.