Metastasis suppressors are key regulators of tumor growth, invasion, and metastases. Loss of metastasis suppressors has been associated with aggressive tumor behaviors and metastatic progression. We previously showed that regulator of calcineurin 1, isoform 4 (RCAN1-4) was upregulated by the KiSS1 metastatic suppression pathway and could inhibit cell motility when overexpressed in cancer cells. To test the effects of endogenous RCAN1-4 loss on thyroid cancer in vivo, we developed RCAN1-4 knockdown stable cells. Subcutaneous xenograft models demonstrated that RCAN1-4 knockdown promotes tumor growth. Intravenous metastasis models demonstrated that RCAN1-4 loss promotes tumor metastases to the lungs and their subsequent growth. Finally, stable induction of RCAN1-4 expression reduced thyroid cancer cell growth and invasion. Microarray analysis predicted that nuclear factor, erythroid 2-like 3 (NFE2L3) was a pivotal downstream effector of RCAN1-4. NFE2L3 overexpression was shown to be necessary for RCAN1-4-mediated enhanced growth and invasiveness and NEF2L3 overexpression independently increased cell invasion. In human samples, NFE2L3 was overexpressed in TCGA thyroid cancer samples versus normal tissues and NFE2L3 overexpression was demonstrated in distant metastasis samples from thyroid cancer patients. In conclusion, we provide the first evidence to our knowledge that RCAN1-4 is a growth and metastasis suppressor in vivo and that it functions in part through NFE2L3.

Background: The renin-angiotensin-aldosterone system (RAAS) is an important driver of BP but the association of the RAAS with ambulatory blood pressure (ABP) and ABPM phenotypes among African Americans (AA) has not been assessed. Methods: ABP and ABPM phenotypes were assessed in 912 Jackson Heart Study participants with aldosterone and plasma renin activity (PRA). Multivariable linear and logistic regression analysis were used to analyze the association of aldosterone, and PRA with clinic, awake and asleep systolic blood pressure (SBP) and diastolic blood pressure (DBP) and ABPM phenotypes, adjusting for important confounders. Results: The mean age of participants was 59 ±11 years and 69% were female. In fully adjusted models, lower log-PRA was associated with higher clinic, awake, and asleep SBP and DBP (all p<0.05). A higher log-aldosterone was associated with higher clinic, awake, and asleep DBP (all p<0.05). A 1-unit higher log-PRA was associated with lower odds of daytime hypertension (OR: 0.59, 95%CI: 0.49, 0.71), nocturnal hypertension (OR: 0.68, 95%CI: 0.58, 0.79), daytime and nocturnal hypertension (OR: 0.59, 95%CI: 0.48, 0.71), sustained hypertension (OR: 0.52, 95%CI: 0.39, 0.70) and masked hypertension (OR 0.75, 95%CI: 0.62, 0.90). A 1-unit higher log-aldosterone was associated with higher odds of nocturnal hypertension (OR: 1.38, 95%CI: 1.05, 1.81). Neither PRA nor aldosterone were associated with percent dipping, non-dipping BP pattern, or white-coat hypertension. Patterns for aldosterone:renin ratio were similar to PRA. Conclusions: Suppressed renin activity and higher aldosterone:renin ratios were associated with both higher SBP and DBP in the office and during the awake and asleep periods as evidenced by ABPM. Higher aldosterone levels were associated with higher DBP, but not SBP, in the clinic and during the awake and asleep periods. Further clinical investigation of novel and approved medications that target low renin physiology such as epithelial sodium channel inhibitors and mineralocorticoid receptor antagonists may be paramount in improving hypertension control in AAs.

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