RCAN1-4 is a thyroid cancer growth and metastasis suppressor

Abstract

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.

Cancer risk susceptibility loci in a Swedish population

“…KCNE2 encodes a voltage-gated potassium channel ancillary subunit and is highly expressed in gastric parietal cells, and was suggested to suppress the proliferation of gastric cancer [ 58 ]. The RCAN1 gene was up-regulated in cancer cells, resulting in inhibition of the cell motility, and RCAN1 knockdown was suggested to promote thyroid cancer tumor growth [ 59 ].…”

NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor

“…Cap'n'collar (CNC) transcription factors have crucial roles in a variety of cellular processes, including the stress response and carcinogenesis, with its most extensively investigated family member being the NFE2L2 (NRF2) protein (DeNicola et al, 2011). NFE2L3 (NRF3), a close homolog of NFE2L2, is less well studied and its functions remain largely unknown , but some recent findings linked the transcription factor to apoptosis and different types of cancer (Chowdhury et al, 2017;Siegenthaler et al, 2018;Sun et al, 2019;Wang et al, 2017Wang et al, , 2018. Similar to other CNC proteins, NFE2L3 dimerizes with small MAF transcription factors, and the resulting complexes bind to the antioxidant response element (ARE) type of DNA-recognition sites (Ché nais et al, 2005).…”

Akt isoform-specific effects on thyroid cancer development and progression in a murine thyroid cancer model

“…Cell migration was measured using a modified procedure from previously reported methods 34 , 37 using a Boyden chamber. Cell invasion was examined as described 38 . The details of methods are in “ Supplemental Materials and Methods ”.…”