A Toxicogenomic Approach Reveals a Novel Gene Regulatory Network Active in In Vitro and In Vivo Models of Thyroid Carcinogenesis

Abstract

Epidemiological and experimental studies emphasize the link between environmental chemicals exposure and thyroid cancer. However, this association is strongly debated and the mechanisms of action of environmental thyroid carcinogens still need to be identified. The analysis of in vitro transcriptomic data developed to investigate the effects of chlorpyrifos on immortalized thyrocytes highlighted the impaired expression of genes involved in endodermal carcinogenesis. This endodermal carcinogenic gene-network (ECGN, including Zfp36l2, Dmbt1, Ddit4), was validated in cellular and mouse models of thyroid carcinogenesis, characterized by the constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and in immortalized thyrocytes exposed to tetrachlorodibenzo-p-dioxin (TCDD) and chlorpyrifos (CPF). The mRNA levels of Zfp36l2, Dmbt1 and Ddit4 were increased in models characterized by MAPK activation or following TCDD exposure, whereas they were inhibited by CPF exposure. Overall, the ECGN transcripts identify a novel gene-regulatory network associated with thyroid carcinogenesis promoted by genetic mutation or by environmental carcinogens. The latter have opposite effects on the modulation of the ECGN transcripts according to their mechanisms of action in promoting carcinogenesis. Therefore, the analyses of ECGN might be helpful in discriminating compounds that promote cellular survival associated or not to proliferation of thyrocytes.

ZFP36L2 Role in Thyroid Functionality

“…In our models, this event is driven by ZFP36L2 inactivation in association with the reduced expression of thyroid-specific transcripts. This last is a hallmark of the transformation of thyrocytes [33]. Finally, apoptosis is an early and pivotal step in thyroid carcinogenesis, and ZFP36L2 inactivation results in its increase.…”

“…In our previous work, we observed that levels of the mRNA of ZFP36L2, a protein that can promote RNA degradation [50], were increased during thyroid development [32] and reduced during hypothyroidism promoted by environmental stressors [34], as well as during thyroid carcinogenesis [33,41]. Its role in thyroid development and function has not yet been characterized.…”

“…To date, its involvement in thyroid development and function has not been reported. We have previously observed that Zfp36l2 mRNA was enriched in mouse thyroid buds (E10.5) [32] and decreased in models of thyroid carcinogenesis [33]. Furthermore, Zfp36l2 expression was reduced in thyrocytes exposed to environmental stressors [34].…”

“…Hematoxylin and Eosin staining were performed on 5 µm tissue slices prepared from 6 samples of Formalin-fixed and Paraffin-embedded thyroids from 3-month-old female animals of each genotype, as previously described [33].…”

GINS2 affects cell proliferation, apoptosis, migration and invasion in thyroid cancer via regulating MAPK signaling pathway

“…There are several risk factors that are closely associated with TC occurrence and development, including genetic factors, age, sex, environmental exposure and epigenetic alterations. Even though there have been improvements in the diagnosis and surgical treatment of TC, the disadvantages associated with treatment strategies should not be ignored ( 4 , 5 ). Furthermore, TC demonstrates an increasing morbidity year on year, along with high rate of recurrence and a younger age at diagnosis, indicating a requirement for additional research on TC ( 3 ).…”