A knockdown with smoke model reveals FHIT as a repressor of Heme oxygenase 1

Abstract

Fragile histidine triad (FHIT) gene deletions are among the earliest and most frequent events in carcinogenesis, particularly in carcinogen-exposed tissues. Though FHIT has been established as an authentic tumor suppressor, the mechanism underlying tumor suppression remains opaque. Most experiments designed to clarify FHIT function have analyzed the consequence of re-expressing FHIT in FHIT-negative cells. However, carcinogenesis occurs in cells that transition from FHIT-positive to FHIT-negative. To better understand cancer development, we induced FHIT loss in human bronchial epithelial cells with RNA interference. Because FHIT is a demonstrated target of carcinogens in cigarette smoke, we combined FHIT silencing with cigarette smoke extract (CSE) exposure and measured gene expression consequences by RNA microarray. The data indicate that FHIT loss enhances the expression of a set of oxidative stress response genes after exposure to CSE, including the cytoprotective enzyme heme oxygenase 1 (HMOX1) at the RNA and protein levels. Data are consistent with a mechanism in which Fhit protein is required for accumulation of the transcriptional repressor of HMOX1, Bach1 protein. We posit that by allowing superinduction of oxidative stress response genes, loss of FHIT creates a survival advantage that promotes carcinogenesis.

Fhit–Fdxr interaction in the mitochondria: modulation of reactive oxygen species generation and apoptosis in cancer cells

“…Fhit protein is a modulator of ROS and thus of apoptotic responses to ROS 45,46 . Because Fhit expression is lost in most cancers 3,4 , including nearly all AMLs 5 , most cancers have lost this important ROS modulator and an important apoptotic signal pathway, allowing inappropriate survival and growth of cancers.…”

Cancer-associated fibroblasts promote cancer cell growth through a miR-7-RASSF2-PAR-4 axis in the tumor microenvironment

“…The fragile histidine triad gene (FHIT), a tumor suppressor, was reported to be a common target of carcinogens, particularly cigarette smoke [ 44 ]. Evidences showed that FHIT loss could enhance the expression of a set of oxidative stress response genes after exposure to cigarette smoke extract, thereafter creating a survival advantage that promotes carcinogenesis [ 45 ]. Then the question becomes: whether the exposure to cigarette smoke extract would give rise to the dysregulation of some crutial genes (including miRNAs) in CAFs, or whether the CAFs derived from HNC tissues of smoking patient could create a more appropriate microenvironment to accelerate the carcinogenic process?…”

Heme oxygenase-1 gene promoter polymorphisms are associated with coronary heart disease and restenosis after percutaneous coronary intervention: a meta-analysis

“…There are three isoforms of heme oxygenase in human, including HO-1, HO-2 and HO-3. HO-1 is up-regulated by oxidative stress and its own substrate heme [ 43 ] and may be modulated by fragile histidine triad gene ( FHIT ) [ 44 ]. Animal experiments and clinical trials have confirmed that the HO-1 enzyme is expressed in various tissues and cells, including asatherosclerotic lesions and vascular smooth muscle cells [ 43 ].…”