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The Role of the Hedgehog Pathway in Chemoresistance of Gastrointestinal Cancers

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The Role of the Hedgehog Pathway in Chemoresistance of Gastrointestinal Cancers cells Review The Role of the Hedgehog Pathway in Chemoresistance of Gastrointestinal Cancers Yabing Liang 1, Ling Yang 1,* and Jingwu Xie 2,* 1 Inner Mongolia Key Laboratory of Medical Cell Biology, Clinical Medical Research Center of the Affiliated Hospital, Inner Mongolia Medical University, Hohhot 010050, China; [email protected] 2 Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA * Correspondence: [email protected] (L.Y.); [email protected] (J.X.) Abstract: The hedgehog pathway, which plays a significant role in embryonic development and stem cell regulation, is activated in gastrointestinal cancers. Chemotherapy is widely used in cancer treatment. However, chemoresistance becomes a substantial obstacle in cancer therapy. This review focuses on the recent advances in the hedgehog pathway’s roles in drug resistance of gastrointestinal cancers and the novel drugs and strategies targeting hedgehog signaling. Keywords: the hedgehog pathway; chemotherapy; resistance; gastric cancer; colorectal cancer; pancreatic cancer 1. Introduction Citation: Liang, Y.; Yang, L.; Xie, J. The hedgehog (HH) pathway plays a crucial role in embryonic development, tissue The Role of the Hedgehog Pathway in homeostasis, and carcinogenesis [1,2]. HH ligands activate signaling by binding to receptor Chemoresistance of Gastrointestinal patched 1 homolog (PTCH1). In the absence of HH ligands, PTCH1 prevents smoothened Cancers. Cells 2021, 10, 2030. https:// (SMO) from transducing a signal to the downstream glioma-associated oncogene homolog doi.org/10.3390/cells10082030 (GLI) transcription factors. HH ligands bind to PTCH1, and relieve PTCH1’s inhibition on SMO, allowing SMO to signal downstream effectors GLI, which activates the target genes Academic Editors: Maria via specific genomic DNA sequences (TGGGTGGTC) [3,4]. Domenica Castellone, Xiaoyan Zheng Activation of GLI proteins via the HH–PTCH1–SMO axis is regarded as the canonical and Stephen Yarwood HH signaling pathway. In addition to the canonical pathway, some molecules can bypass the ligand-receptor signaling axis to activate GLI, and these types of regulation are regarded Received: 9 June 2021 as non-canonical HH signaling. Non-canonical HH signaling is found in malignant diseases. Accepted: 6 August 2021 KRAS signaling [5,6], transforming growth factor β (TGFβ)[7], AKT [8], protein kinase Published: 9 August 2021 C (PKC) [9], and SOX2-bromodomain-containing protein 4(BRD4) [10] are reported to regulate HH signaling via non-canonical pathways. Publisher’s Note: MDPI stays neutral Chemotherapy is widely used in cancer treatment, and significant improvement is with regard to jurisdictional claims in achieved in the prognosis of patients. However, not all patients benefit from it. Chemore- published maps and institutional affil- sistance becomes a substantial obstacle in cancer therapy due to intrinsic resistance, which iations. occurs at the beginning or even before the treatment, or acquired resistance after initial response to treatment, resulting in relapse [11,12]. Platinum, 5-Fluorouracil (5-FU), and gemcitabine are the most commonly used drugs in the chemotherapy of gastric, colorectal, and pancreatic cancers, and the underlined mechanisms of drug resistance have been Copyright: © 2021 by the authors. studied. Mechanisms of chemoresistance include cancer stem cells(CSCs), tumor microen- Licensee MDPI, Basel, Switzerland. vironment, and ATP-binding cassette (ABC) transporter family proteins [13–15]. This article is an open access article Our group studied drug resistance in gastrointestinal cancers and found the HH distributed under the terms and pathway contributes to drug resistance. This review focuses on recent advances that link conditions of the Creative Commons the HH pathway to drug resistance in gastrointestinal cancers and examines novel drugs Attribution (CC BY) license (https:// and strategies that may overcome HH-mediated drug resistance. creativecommons.org/licenses/by/ 4.0/). Cells 2021, 10, 2030. https://doi.org/10.3390/cells10082030 https://www.mdpi.com/journal/cells Cells 2021, 10, x 2 of 10 Cells 2021, 10, 2030 2 of 10 2.2. Cancer Cancer Stem Stem Cells Cells CSCsCSCs are are a a subpopulation subpopulation of of cancer cancer cells cells capable capable of of self self-renewal,-renewal, metastasis, metastasis, and and treatmenttreatment resistance. resistance. Evidence Evidence indicates indicates that that CSCs CSCs are are involved involved in in chemoresistance chemoresistance and and relapserelapse of of cancers. cancers. As As a a cl classicalassical developmental developmental pathway, pathway, the the HH HH pathway pathway supports supports the the maintenancemaintenance and and survival survival of of CSCs CSCs (Figure (Figure 11))[[1616]].. T Therefore,herefore, targeting targeting the the HH HH pathway pathway maymay be be a a promising promising strategy strategy in in eradicating eradicating CSCs CSCs[17,18 [17,18].]. Figure 1. The HH pathway in gastrointestinal CSCs. The role of the hedgehog pathway in drug Figure 1. The HH pathway in gastrointestinal CSCs. The role of the hedgehog pathway in drug resistance of gastrointestinal CSCs and inhibitors for hedgehog signaling is summarized. In gas- resistance of gastrointestinal CSCs and inhibitors for hedgehog signaling is summarized. In gastro- intestinaltrointestinal CSC CSCs,s, CCN1, CCN1, Notch1, Notch1, Ski, Ski, Vasohibi Vasohibin2,n2, and and chemotherapy chemotherapy can can activate activate the the HH HH pathway pathway toto increase increase stemness stemness through through upregulating upregulating CD44, CD44, CD24, CD24, CD133, CD133, SOX2, SOX2, SOX9, SOX9, OCT OCT-4,-4, Nanog Nanog,, and and cc-myc,-myc, to to increase increase drug drug resistance resistance by by elevating elevating the the expression expression of of the the drug drug efflux efflux protein protein ABCC1 ABCC1 and and ABCG2,ABCG2, and and to to ad adaptapt to to hypoxia hypoxia via via high high expression expression of HIF1 of HIF1α. Tαhe. TheHH HHinhibitors inhibitors (5E1, (5E1, vismodegib, vismod- cyclopamine,egib, cyclopamine, IPI926, IPI926, GANT61, GANT61, GLI GLIsiRNA siRNA,, and andlncRNA lncRNA cCSC1) cCSC1) can can attenuate attenuate these these processes. processes. HHedgehogedgehog (HH); (HH); cancer cancer stem stem cells cells (CSCs); (CSCs); cellular cellular communication communication network network factor factor 1 1(CCN1 (CCN1);); ATP ATP-- bindingbinding cassette cassette subfamily subfamily C C member member 1 1 ( (ABCC1);ABCC1); ATP ATP-binding-binding cassette cassette sub subfamilyfamily G G member member 2 2 (ABCG2); hypoxia inducible factor 1α (HIF1α). (ABCG2); hypoxia inducible factor 1α (HIF1α). WeWe and and others others have have discover discovereded that that the the HH HH pathway pathway is is activated activated in in gastric gastric CSCs, CSCs, whichwhich is is characterized characterized by by a si sidede population[ [1919]],, cell cell surface surface marker CD44 [20,21 [20,21]],, CD24, CD24, CD133CD133[22 [22], ],aldehyde aldehyde dehydrogenase dehydrogenase (ALDH (ALDH))[23] [,23 and], andMusashi Musashi-1-1[24]. [This24]. pathway This pathway is es- sentialis essential for maintaining for maintaining the viability, the viability, motility, motility, and chemotherap and chemotherapeuticeutic resistance resistance of gastric of CSCs.gastric Recently, CSCs. Recently, SOX2-positive SOX2-positive gastric cancer gastric cells cancer were cells found were to foundpresent to CSC present proper- CSC tiepropertiess[25]. The [ 25CSCs]. Thewith CSCs activated with HH activated signaling HH contributed signaling contributedto chemotherapy to chemotherapy resistance in variantresistance kinds in variant of drugs kinds, such of drugs,as platinum such as[19,20 platinum], 5-Fu [19[20,25,26,20], 5-Fu], paclitaxel [20,25,26[],27 paclitaxel], and doxo- [27], rubicinand doxorubicin[24]. Our group [24]. Our found group that found the GLI1 that protein the GLI1 interacted protein interacted with the promoter with the promoter of ATP- bindingof ATP-binding cassette cassettesubfamily subfamily G member G member 2 (ABCG2)through 2 (ABCG2)through a GLI-binding a GLI-binding consensus consensus site in gastricsite in gastricCSCs[19 CSCs]. ABCG2 [19]. ABCG2is a well is-known a well-known drug efflux drug protein efflux proteinand transports and transports small mole- small culmolecules,es, including including chemotherapeutic chemotherapeutic drugs. drugs. This mechanism This mechanism may explain may explain why gastric why gastric CSCs enrichedCSCs enriched with the with HH the pathway HH pathway are more are resistant more resistant to chemotherapy. to chemotherapy. TheThe HH HH pathway pathway also also plays plays a a vital vital role role in in colorectal colorectal CSCs. CSCs. Colorectal Colorectal CSCs CSCs sh showedowed elevatedelevated expression expression of thethe genesgenes downstreamdownstream of of HH HH signaling signaling [28 [28,29,29], and], and the the HH HH pathway path- wayinhibitor inhibitor reduced reduced the expression the expression of stemness of stemness markers markers and resistance and resistance to 5-FU andto 5 platinum-FU and Cells 2021, 10, 2030 3 of 10 in colorectal CSCs [28,30]. Activation of HH signaling is associated with high expression of CD133, SOX9, hypoxia inducible factor 1α (HIF1α), and ATP-binding cassette subfamily C member 1 (ABCC1) in colorectal CSCs [29,30]. lncRNA-cCSC1 inhibited
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