Thyroid hormone suppresses expression of stathmin and associated tumor growth in hepatocellular carcinoma

Abstract

Stathmin (STMN1), a recognized oncoprotein upregulated in various solid tumors, promotes microtubule disassembly and modulates tumor growth and migration activity. However, the mechanisms underlying the genetic regulation of STMN1 have yet to be elucidated. In the current study, we report that thyroid hormone receptor (THR) expression is negatively correlated with STMN1 expression in a subset of clinical hepatocellular carcinoma (HCC) specimens. We further identified the STMN1 gene as a target of thyroid hormone (T3) in the HepG2 hepatoma cell line. An analysis of STMN1 expression profile and mechanism of transcriptional regulation revealed that T3 significantly suppressed STMN1 mRNA and protein expression, and further showed that THR directly targeted the STMN1 upstream element to regulate STMN1 transcriptional activity. Specific knockdown of STMN1 suppressed cell proliferation and xenograft tumor growth in mice. In addition, T3 regulation of cell growth arrest and cell cycle distribution were attenuated by overexpression of STMN1. Our results suggest that the oncogene STMN1 is transcriptionally downregulated by T3 in the liver. This T3-mediated suppression of STMN1 supports the theory that T3 plays an inhibitory role in HCC tumor growth, and suggests that the lack of normal THR function leads to elevated STMN1 expression and malignant growth.

Molecular functions and clinical impact of thyroid hormone-triggered autophagy in liver-related diseases

“…The TH/THR signals and interacting partners may facilitate the switch from tumor suppression in the premalignant stages to promotion in the later stages of HCC [7]. For instance, administration of TH not only reduces the size of preneoplastic lesions in the livers of rats suffering with HCC, but suppresses the aberrant cellular growth via control the expression of cell cycle regulators, such as CDK2, Cyclin E, UHRF1, STMN1 mir-214 and BC200 lncRNA [7,[171][172][173][174]. Our recent studies further support the preventive effect of TH on hepatocarcinogenesis via activating autophagy [16,17], whereas TH/THR is reported to promote metastasis and chemoresistance through control the expressions of BSSP4, TRAIL, BCL2L11, LCN2, mir-21, and mir-130b [7,173,[175][176][177][178][179][180].…”

Thyroid hormone in the regulation of hepatocellular carcinoma and its microenvironment

“…Despite compelling evidence showing that T3 stimulates normal hepatocyte proliferation in animal models of liver injury and healthy liver [10][11][12][13][15][16][17][18][19] (Figure 2), T3 and agonists appear to exert opposite effect on local tumor progression (i.e., inhibitory effect on HCC development in vivo [75][76][77] or on proliferation in vitro [20,78]) (Figure 3).…”

Relevant coexpression of STMN1, MELK and FOXM1 in glioblastoma and review of the impact of STMN1 in cancer biology

“…Clinical and experimental observations suggest that T3 might regulate microtubule network assembly through repression of STMN1 expression. 51 In addition to hormones and growth factors, ion channels can also activate STMN1. Activation of ion channels initiate a Ca +2 response in parallel with activation of several migration foci and vascular invasion, with negative impact in recurrence free survival of diffuse type of gastric carcinoma.…”