Activation of the Sonic Hedgehog pathway in thyroid neoplasms and its potential role in tumor cell proliferation

The sonic hedgehog (SHH) pathway is activated in several types of malignancy and plays an important role in tumor cell proliferation and tumorigenesis. SHH binding to a 12-pass transmembrane receptor, Patched (PTCH), leads to freeing of Smoothened (SMO) and subsequent activation of GLI transcription factors. In the present study, we analyzed the expression of SHH, PTCH, SMO, and GLI1 in 31 follicular thyroid adenomas (FTA), 8 anaplastic thyroid carcinomas (ATC), and 51 papillary thyroid carcinomas (PTC) by immunohistochemical staining. More than 65% of FTA, PTC, and ATC specimens stained positive for SHH, PTCH, SMO, and GLI. However, the expression of the genes encoding these four molecules did not correlate with any clinicopathologic parameters, including the age, gender, the status ofBRAFgene mutation, tumor stage, local invasion, and metastasis. Three thyroid tumor cell lines (KAT-18, WRO82, and SW1736) all expressed the genes encoding these four molecules. 5-Bromo-2-deoxyuridine labeling and MTT cell proliferation assays revealed that cyclopamine (CP), an inhibitor of the SHH pathway, was able to inhibit the proliferation of KAT-18 and WRO82 cells more effectively than SW1736 cells. CP led to the arrest of cell cycle or apoptosis. Knockdown ofSHHandGLIexpression by miRNA constructs that targetSHHorGLImRNA in KAT-18 and SW1736 cells led to the inhibition of cell proliferation. Our results suggest that the SHH pathway is widely activated in thyroid neoplasms and may have potential as an early marker of thyroid cancer or as a potential therapeutic target for thyroid cancer treatment.

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Targeting the Sonic Hedgehog Pathway to Suppress the Expression of the Cancer Stem Cell (CSC)—Related Transcription Factors and CSC-Driven Thyroid Tumor Growth

Cancers ◽

10.3390/cancers13030418 ◽

2021 ◽

Vol 13 (3) ◽

pp. 418

Author(s):

Yurong Lu ◽

Yiwen Zhu ◽

Shihan Deng ◽

Yuhuang Chen ◽

Wei Li ◽

...

Keyword(s):

Transcription Factor ◽

Stem Cell ◽

Transcription Factors ◽

Thyroid Cancer ◽

Tumor Growth ◽

Sonic Hedgehog ◽

Thyroid Tumor ◽

Self Renewal ◽

Sox2 Expression ◽

Shh Pathway

The sonic hedgehog (Shh) pathway plays important roles in tumorigenesis, tumor growth, drug resistance, and metastasis. We and others have reported earlier that this pathway is highly activated in thyroid cancer. However, its role in thyroid cancer stem cell (CSC) self-renewal and tumor development remains incompletely understood. B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and SRY-Box Transcription Factor 2 (SOX2) are two CSC-related transcription factors that have been implicated in promoting CSC self-renewal. The objective of our current investigation was to determine the role of the Shh pathway in regulating BMI1 and SOX2 expression in thyroid cancer and promoting thyroid tumor growth and development. Here we report that inhibition of the Shh pathway by Gli1 siRNA or by cyclopamine and GANT61 reduced BMI1 and SOX2 expression in SW1736 and KAT-18 cells, two anaplastic thyroid cancer cell lines. The opposite results were obtained in cells overexpressing Gli1 or its downstream transcription factor Snail. The Shh pathway regulated SOX2 and BMI1 expression at a transcriptional and post-transcriptional level, respectively. GANT61 treatment suppressed the growth of SW1736 CSC-derived tumor xenografts but did not significantly inhibit the growth of tumors grown from bulk tumor cells. Clinicopathological analyses of thyroid tumor specimens by immunohistochemical (IHC) staining revealed that BMI1 and SOX2 were highly expressed in thyroid cancer and correlated with Gli1 expression. Our study provides evidence that activation of the Shh pathway leads to increased BMI1 and SOX2 expression in thyroid cancer and promotes thyroid CSC-driven tumor initiation. Targeting the Shh pathway may have therapeutic value for treating thyroid cancer and preventing recurrence.

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MEK inhibition suppresses cholangiocarcinoma growth by restraining tumor cell proliferation and modulating tumor microenvironment

10.1055/s-0038-1677238 ◽

2019 ◽

Author(s):

K Utpatel ◽

P Wang ◽

X Song ◽

R Shang ◽

M Xu ◽

...

Keyword(s):

Cell Proliferation ◽

Tumor Microenvironment ◽

Tumor Cell ◽

Tumor Cell Proliferation ◽

Mek Inhibition

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Faculty Opinions recommendation of Interference of tenascin-C with syndecan-4 binding to fibronectin blocks cell adhesion and stimulates tumor cell proliferation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1003182.38354 ◽

2002 ◽

Author(s):

John R Couchman

Keyword(s):

Cell Proliferation ◽

Cell Adhesion ◽

Tumor Cell ◽

Tumor Cell Proliferation ◽

Tenascin C

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Faculty Opinions recommendation of Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1033082.375092 ◽

2006 ◽

Author(s):

Filippo Giancotti

Keyword(s):

Cell Proliferation ◽

Tumor Cell ◽

Tumor Cell Proliferation ◽

Nf Kappab

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Faculty Opinions recommendation of Krüppel-like factor 4 blocks tumor cell proliferation and promotes drug resistance in multiple myeloma.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718000290.793476769 ◽

2013 ◽

Author(s):

Diane Jelinek ◽

Alexandra Greenberg

Keyword(s):

Multiple Myeloma ◽

Cell Proliferation ◽

Drug Resistance ◽

Tumor Cell ◽

Tumor Cell Proliferation

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Expression of β-Catenin in Hepatocellular Carcinoma

Revista de Chimie ◽

10.37358/rc.20.3.7979 ◽

2001 ◽

Vol 71 (3) ◽

pp. 116-125

Author(s):

Norina Basa ◽

Daniela Lazar ◽

Remus Cornea ◽

Sorina Taban ◽

Melania Ardelean ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Tumor Cell ◽

Mitotic Index ◽

Histological Grade ◽

Proliferation Index ◽

Tumor Cell Proliferation ◽

Ki 67 ◽

B Virus ◽

Development And Evolution

Alteration of β-catenin expression is involved in the development and evolution of hepatocellular carcinoma (HCC); β-catenin is able to influence tumor cell proliferation. We analyzed the immunohistochemical (IHC) expression of β-catenin on a group of 32 patients diagnosed with HCC using the anti-β-catenin monoclonal antibody (clone E247). We correlated the expression of β-catenin with the proliferation index of Ki-67 (PI Ki-67), the mitotic index (MI) and other clinical and pathological features. We observed an altered β-catenin expression in 58.38% of all HCC cases. This expression was insignificantly correlated with tumor size (]5 cm) (p = 0.683), histological grade G1-G2 (p = 0.307), vascular invasion (p = 0.299) and advanced pT stage (p = 0.453); we obtained a significantly higher MI in HCC with altered β-catenin expression (p = 0.018), as compared to HCC without overexpression (1.66 � 1.37) (p = 0.038) and a PI Ki-67 of 22.49 � 20.1 and 28.24 � 18.2, respectively in tumors with altered β-catenin expression with insignificant differences compared to HCC without overexpression (25.95 � 15.2) (p = 0.682 and p = 0.731, respectively). According to the results we obtained, aberrant β-catenin expression in HCC was correlated with a high mitotic index, therefore playing an important role in tumor progression by stimulating tumor cell proliferation; non-nuclear β-catenin overexpression can have a pathological significance in HCC, especially in cases of HCC associated with hepatitis B virus (HBV) infection.

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Combined Application of Pan-AKT Inhibitor MK-2206 and BCL-2 Antagonist Venetoclax in B-Cell Precursor Acute Lymphoblastic Leukemia

International Journal of Molecular Sciences ◽

10.3390/ijms22052771 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2771

Author(s):

Anna Richter ◽

Elisabeth Fischer ◽

Clemens Holz ◽

Julia Schulze ◽

Sandra Lange ◽

...

Keyword(s):

Cell Proliferation ◽

Tumor Cell ◽

Cell Lines ◽

Morphological Changes ◽

Synergistic Effects ◽

Lymphoblastic Leukemia ◽

Tumor Cell Proliferation ◽

Akt Inhibitor ◽

Akt Phosphorylation ◽

Combined Application

Aberrant PI3K/AKT signaling is a hallmark of acute B-lymphoblastic leukemia (B-ALL) resulting in increased tumor cell proliferation and apoptosis deficiency. While previous AKT inhibitors struggled with selectivity, MK-2206 promises meticulous pan-AKT targeting with proven anti-tumor activity. We herein, characterize the effect of MK-2206 on B-ALL cell lines and primary samples and investigate potential synergistic effects with BCL-2 inhibitor venetoclax to overcome limitations in apoptosis induction. MK-2206 incubation reduced AKT phosphorylation and influenced downstream signaling activity. Interestingly, after MK-2206 mono application tumor cell proliferation and metabolic activity were diminished significantly independently of basal AKT phosphorylation. Morphological changes but no induction of apoptosis was detected in the observed cell lines. In contrast, primary samples cultivated in a protective microenvironment showed a decrease in vital cells. Combined MK-2206 and venetoclax incubation resulted in partially synergistic anti-proliferative effects independently of application sequence in SEM and RS4;11 cell lines. Venetoclax-mediated apoptosis was not intensified by addition of MK-2206. Functional assessment of BCL-2 inhibition via Bax translocation assay revealed slightly increased pro-apoptotic signaling after combined MK-2206 and venetoclax incubation. In summary, we demonstrate that the pan-AKT inhibitor MK-2206 potently blocks B-ALL cell proliferation and for the first time characterize the synergistic effect of combined MK-2206 and venetoclax treatment in B-ALL.

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Validation of MicroRNA-188-5p Inhibition Power on Tumor Cell Proliferation in Papillary Thyroid Carcinoma

Cell Transplantation ◽

10.1177/0963689720918300 ◽

2020 ◽

Vol 29 ◽

pp. 096368972091830 ◽

Cited By ~ 1

Author(s):

Ping Zhou ◽

Andrew Irving ◽

Huifang Wu ◽

Juan Luo ◽

Johana Aguirre ◽

...

Keyword(s):

Cell Proliferation ◽

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Tumor Cell ◽

Cellular Proliferation ◽

Tumor Cell Proliferation ◽

Papillary Thyroid ◽

Tumor Tissues ◽

Potential Biomarker ◽

And Function

Given the crucial role of microRNAs in the cellular proliferation of various types of cancers, we aimed to analyze the expression and function of a cellular proliferation-associated miR-188-5p in papillary thyroid carcinoma (PTC). Here we demonstrate that miR-188-5p is downregulated in PTC tumor tissues compared with the associated noncancerous tissues. We also validate that the miR-188-5p overexpression suppressed the PTC cancer cell proliferation. In addition, fibroblast growth factor 5 (FGF5) is observed to be downregulated in the PTC tumor tissues compared with the associated noncancerous tissues. Subsequently, FGF5 is identified as the direct functional target of miR-188-5p. Moreover, the silencing of FGF5 was found to inhibit PTC cell proliferation, which is the same pattern as miR-188-5p overexpression. These results suggest that miR-188-5p-associated silencing of FGF5 inhibits tumor cell proliferation in PTC. It also highlights the importance of further evaluating miR-188-5p as a potential biomarker and therapy target in PTC.

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