Sonic Hedgehog Signaling Pathway As a Potential Target to Inhibit the Progression of Hepatocellular Carcinoma

Overview

Journal Oncol Lett

Specialty Oncology

Date 2019 Oct 16

PMID 31611946

Citations 29

Authors

Kuo-Shyang Jeng

Chi-Juei Jeng

Wen-Juei Jeng

I-Shyan Sheen

Shih-Yun Li

Chuen-Miin Leu

Yeou-Guang Tsay

Chiung-Fang Chang

Affiliations

Soon will be listed here.

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated mortality worldwide. Hepatocarcinogenesis involves numerous interlinked factors and processes, including the Sonic hedgehog (Shh) signaling pathway, which participates in the carcinogenesis, progression, invasiveness, recurrence and cancer stem cell maintenance of HCC. The Shh signaling pathway is activated by ligands that bind to their receptor protein, Protein patched homolog (Ptch). The process of Shh ligand binding to Ptch weakens the inhibition of smoothened homolog (SMO) and activates signal transduction via glioma-associated oncogene homolog (Gli) transcription factors. The overexpression of Shh pathway molecules, including Shh, Ptch-1, Gli and SMO has been indicated in patients with HCC. It has also been suggested that the Shh signaling pathway exhibits cross-talk between numerous other signaling pathways. The inactivation of the Shh signaling pathway reduces HCC growth, increases radio-sensitivity and increases the beneficial effect of chemotherapy in HCC treatment. Therefore, inhibition of the Shh pathway may be an effective target therapy that can be used in the treatment of HCC.

Citing Articles

FBXO32 ubiquitination of SUFU promotes progression and lenvatinib resistance in hepatocellular carcinoma via hedgehog signaling.

Wang S, Peng R, Chen C, Tu D, Cao J, Su B Med Oncol. 2025; 42(4):98.

PMID: 40067532 DOI: 10.1007/s12032-025-02644-1.

Hepatocellular carcinoma: signaling pathways and therapeutic advances.

Zheng J, Wang S, Xia L, Sun Z, Chan K, Bernards R Signal Transduct Target Ther. 2025; 10(1):35.

PMID: 39915447 PMC: 11802921. DOI: 10.1038/s41392-024-02075-w.

Transcription factor Yin Yang 1 enhances epithelial-mesenchymal transition, migration, and stemness of non-small cell lung cancer cells by targeting sonic hedgehog.

Huang T, Ren K, Ling X, Li Z, Chen L Mol Cell Biochem. 2024; 480(3):1831-1843.

PMID: 39261409 DOI: 10.1007/s11010-024-05104-y.

Hedgehog components are overexpressed in a series of liver cancer cases.

Sales C, Dias R, de Faro Valverde L, Bomfim L, Silva L, de Carvalho N Sci Rep. 2024; 14(1):19507.

PMID: 39174588 PMC: 11341691. DOI: 10.1038/s41598-024-70220-0.

Sonic hedgehog expression in steatohepatitic hepatocellular carcinoma and its clinicopathological significance.

Kusano H, Ogasawara S, Omuraya M, Okudaira M, Mizuochi S, Mihara Y Oncol Lett. 2024; 28(3):442.

PMID: 39091582 PMC: 11292461. DOI: 10.3892/ol.2024.14575.

References

Lin T, Matsui W . Hedgehog pathway as a drug target: Smoothened inhibitors in development. Onco Targets Ther. 2012; 5:47-58. PMC: 3325001. DOI: 10.2147/OTT.S21957. View

Arzumanyan A, Sambandam V, Clayton M, Choi S, Xie G, Diehl A . Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein. Cancer Res. 2012; 72(22):5912-20. PMC: 3521045. DOI: 10.1158/0008-5472.CAN-12-2329. View

Steinway S, G T Zanudo J, Ding W, Rountree C, Feith D, Loughran Jr T . Network modeling of TGFβ signaling in hepatocellular carcinoma epithelial-to-mesenchymal transition reveals joint sonic hedgehog and Wnt pathway activation. Cancer Res. 2014; 74(21):5963-77. PMC: 4851164. DOI: 10.1158/0008-5472.CAN-14-0225. View

Chong Y, Lim T, Fu Y, Shin E, Tergaonkar V, Han W . Indian Hedgehog links obesity to development of hepatocellular carcinoma. Oncogene. 2018; 38(12):2206-2222. DOI: 10.1038/s41388-018-0585-5. View

Hasanovic A, Mus-Veteau I . Targeting the Multidrug Transporter Ptch1 Potentiates Chemotherapy Efficiency. Cells. 2018; 7(8). PMC: 6115939. DOI: 10.3390/cells7080107. View

Meng J, Chen S, Han J, Qian B, Wang X, Zhong W . Twist1 Regulates Vimentin through Cul2 Circular RNA to Promote EMT in Hepatocellular Carcinoma. Cancer Res. 2018; 78(15):4150-4162. DOI: 10.1158/0008-5472.CAN-17-3009. View

Wang Y, Chen W, Han C, Zhang J, Song K, Kwon H . Adult Hepatocytes Are Hedgehog-Responsive Cells in the Setting of Liver Injury: Evidence for Smoothened-Mediated Activation of NF-κB/Epidermal Growth Factor Receptor/Akt in Hepatocytes that Counteract Fas-Induced Apoptosis. Am J Pathol. 2018; 188(11):2605-2616. PMC: 6207910. DOI: 10.1016/j.ajpath.2018.07.018. View

Filgueira N . Hepatocellular carcinoma recurrence after liver transplantation: Risk factors, screening and clinical presentation. World J Hepatol. 2019; 11(3):261-272. PMC: 6447422. DOI: 10.4254/wjh.v11.i3.261. View

Stone D, Hynes M, Armanini M, Swanson T, Gu Q, Johnson R . The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature. 1996; 384(6605):129-34. DOI: 10.1038/384129a0. View

10.

Shindoh J, Hasegawa K, Inoue Y, Ishizawa T, Nagata R, Aoki T . Risk factors of post-operative recurrence and adequate surgical approach to improve long-term outcomes of hepatocellular carcinoma. HPB (Oxford). 2012; 15(1):31-9. PMC: 3533710. DOI: 10.1111/j.1477-2574.2012.00552.x. View

11.

Kanda T, Goto T, Hirotsu Y, Moriyama M, Omata M . Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review. Int J Mol Sci. 2019; 20(6). PMC: 6470669. DOI: 10.3390/ijms20061358. View

12.

Kew M . Aflatoxins as a cause of hepatocellular carcinoma. J Gastrointestin Liver Dis. 2013; 22(3):305-10. View

13.

Di Bisceglie A . Hepatitis B and hepatocellular carcinoma. Hepatology. 2009; 49(5 Suppl):S56-60. PMC: 3047495. DOI: 10.1002/hep.22962. View

14.

Zeller C, Hinzmann B, Seitz S, Prokoph H, Burkhard-Goettges E, Fischer J . SASH1: a candidate tumor suppressor gene on chromosome 6q24.3 is downregulated in breast cancer. Oncogene. 2003; 22(19):2972-83. DOI: 10.1038/sj.onc.1206474. View

15.

Tripathy A, Thakurela S, Sahu M, Uthanasingh K, Behera M, Ajay A . The molecular connection of histopathological heterogeneity in hepatocellular carcinoma: A role of Wnt and Hedgehog signaling pathways. PLoS One. 2018; 13(12):e0208194. PMC: 6279049. DOI: 10.1371/journal.pone.0208194. View

16.

Wang Q, Huang S, Yang L, Zhao L, Yin Y, Liu Z . Down-regulation of Sonic hedgehog signaling pathway activity is involved in 5-fluorouracil-induced apoptosis and motility inhibition in Hep3B cells. Acta Biochim Biophys Sin (Shanghai). 2008; 40(9):819-29. View

17.

Katoh Y, Katoh M . Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (review). Int J Mol Med. 2008; 22(3):271-5. View

18.

Tian J, Ling L, Shboul M, Lee H, OConnor B, Merriman B . Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling. Am J Hum Genet. 2010; 87(6):768-78. PMC: 2997365. DOI: 10.1016/j.ajhg.2010.11.005. View

19.

Sarangi A, Valadez J, Rush S, Abel T, Thompson R, Cooper M . Targeted inhibition of the Hedgehog pathway in established malignant glioma xenografts enhances survival. Oncogene. 2009; 28(39):3468-76. PMC: 2756306. DOI: 10.1038/onc.2009.208. View

20.

Chen J, Taipale J, Cooper M, Beachy P . Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 2002; 16(21):2743-8. PMC: 187469. DOI: 10.1101/gad.1025302. View