The suppressive role of HYAL1 and HYAL2 in the metastasis of colorectal cancer

Jin, Zeyu; Zhang, Guoliang; Liu, Yiwen; Yang, Cuixia; Du, Yan; Gao, Feng

doi:10.1111/jgh.14660

Cited by 20 publications

(14 citation statements)

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“…26 Typically, MMP2 and MMP9 mediate degradation of tumor extracellular matrix, and overexpression of these crucial regulators has been reported to facilitate metastasis of malignant tumors. 27 In our present study, transwell migration assay and wound healing assay revealed that DHM remarkably suppresses the invasion and migration of CRC cell lines. Moreover, expression of MMP2 and MMP9 was found to markedly decrease with increasing doses of DHM.…”

Section: Discussionsupporting

confidence: 56%

“…It has been widely established that migration and invasion are key factors affecting the treatment of various cancers, and are also leading cause of high mortality associated with CRC 26 . Typically, MMP2 and MMP9 mediate degradation of tumor extracellular matrix, and overexpression of these crucial regulators has been reported to facilitate metastasis of malignant tumors 27 . In our present study, transwell migration assay and wound healing assay revealed that DHM remarkably suppresses the invasion and migration of CRC cell lines.…”

Section: Discussionsupporting

confidence: 53%

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Dihydromethysticin, a natural molecule from Kava, suppresses the growth of colorectal cancer via the NLRC3/PI3K pathway

Pan

Liu

Wang

et al. 2020

Molecular Carcinogenesis

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Dihydromethysticin (DHM), a natural compound derived from Kava, has been reported to be effective against mental disorders and some malignant tu mors. However, little is known about the inhibitory effect of DHM on colorectal cancer (CRC). First, we examined the impact of DHM on human colon cancer cell lines, which demonstrated that DHM inhibits proliferation, migration, and invasion and promotes apoptosis and cell cycle arrest in colon cancer cells in vitro. Using small hairpin RNA, we inhibited nucleotide-oligomerization domain-like receptor subfamily C3 (NLRC3)/phosphoinositide 3-kinase (PI3K) pathway to elucidate the partial signaling of DHM-mediated tumor suppression. Additionally, using an ectopic human CRC model, we verified whether DHM inhibits tumor growth and angiogenesis via the NLRC3/PI3K pathway in vivo. Overall, DHM showed an inhibitory effect on CRC by altering cell proliferation, migration, invasion, apoptosis, cell cycle, and angiogenesis, possibly via the NLRC3/PI3K pathway. Thus, DHM may be a promising candidate for CRC therapy. K E Y W O R D S colorectal cancer, dihydromethysticin, NLRC3 1 | INTRODUCTION Colorectal cancer (CRC) is third most prevailing malignant tumor in the world. In 2016, approximately 134 490 individuals were diagnosed with CRC in the United States, and it was responsible for mortality of more than one-third. 1 In the past few decades, remarkable progress has been made in the treatment of CRC with variety of chemotherapy drugs and immunotherapies constantly emerging. However, due to drug resistance and dose-limiting toxicity, limited success has been achieved in treating advanced CRC. 2 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CDK4, cyclin-dependent kinase 4; CK, creatine kinase.; CRC, colorectal cancer; DAPI, 4′, 6-diamidino-2-phenylindole; DHM, dihydromethysticin; H&E staining, hematoxylin and eosin staining; JNK, c-Jun NH2 terminal kinase; LDH, lactate dehydrogenase; MMP2, matrix metallopeptidase 2; MMP9, matrix metallopeptidase 9; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-kappa B; NLRC3, nucleotide-oligomerization domain-like receptor subfamily C3; PBS, phosphate-buffered saline; PI3K, phosphoinositide 3-kinase; RIPA, radio immunoprecipitation assay; TUNEL, terminal dUTP nick-end labeling; VEGF, vascular endothelial growth factor. Huayang Pan, Fukai Liu, and Jinge Wang contributed equally to this work. Terminal dUTP nick-end labeling (TUNEL) assay was performed according to the manufacturer's instructions (Roche, Shanghai, China). CRC cells were washed once with PBS, fixed with formalin for 30 minutes, and washed again with PBS. Cells were then suspended 576 | PAN ET AL.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionsupporting

confidence: 53%

Dihydromethysticin, a natural molecule from Kava, suppresses the growth of colorectal cancer via the NLRC3/PI3K pathway

Pan

Liu

Wang

et al. 2020

Molecular Carcinogenesis

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“…Concerning renal cell carcinoma (RCC), TIMP2 is inversely correlated with markers of tumour progression [ 55 ]. However, TIMP2 is a poor prognostic marker in gastric cancer [ 56 ], in contrast to its role in colorectal cancer [ 57 ]. TIMP2 is involved in glioma inhibition by different drugs as an intermediate link in the upregulated expression in different studies [ 58 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of expression, prognosis and immune infiltration for TIMPs in glioblastoma

et al. 2021

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Background Tissue inhibitors of metalloproteinase (TIMP) family proteins are peptidases involved in extracellular matrix (ECM) degradation. Various diseases are related to TIMPs, and the primary reason is that TIMPs can indirectly regulate remodelling of the ECM and cell signalling by regulating matrix metalloproteinase (MMP) activity. However, the link between TIMPs and glioblastoma (GBM) is unclear. Objective This study aimed to explore the role of TIMP expression and immune infiltration in GBM. Methods Oncomine, GEPIA, OSgbm, LinkedOmics, STRING, GeneMANIA, Enrichr, and TIMER were used to conduct differential expression, prognosis, and immune infiltration analyses of TIMPs in GBM. Results All members of the TIMP family had significantly higher expression levels in GBM. High TIMP3 expression correlated with better overall survival (OS) and disease-specific survival (DSS) in GBM patients. TIMP4 was associated with a long OS in GBM patients. We found a positive relationship between TIMP3 and TIMP4, identifying gene sets with similar or opposite expression directions to those in GBM patients. TIMPs and associated genes are mainly associated with extracellular matrix organization and involve proteoglycan pathways in cancer. The expression levels of TIMPs in GBM correlate with the infiltration of various immune cells, including CD4+ T cells, macrophages, neutrophils, B cells, CD8+ T cells, and dendritic cells. Conclusions Our study inspires new ideas for the role of TIMPs in GBM and provides new directions for multiple treatment modalities, including immunotherapy, in GBM.

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“…In one previous research, Yan et al ( 59 ) have established a CD133-related gene signature for predicting glioblastoma prognosis; the CD133-related signature successfully distinguishes GBM from LGG, and the CD133-related gene signature defines a new subtype of GBM with shorter survival time. In colorectal cancer, high expression of HYAL1 and HYAL2 can inhibit tumor metastasis ( 60 ), but in triple-negative breast cancer, high expression of HYAL2 genes is associated with shorter disease-free survival, higher tumor recurrence rate, and higher tumor metastasis rate ( 61 ). MMP2 is involved in the invasion of thyroid tumor cells, and its expression is regulated by the ERK and JNK pathways ( 62 , 63 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel Four-Gene Signature Associated With Immune Checkpoint for Predicting Prognosis in Lower-Grade Glioma

et al. 2020

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The overall survival of patients with lower grade glioma (LGG) varies greatly, but the current histopathological classification has limitations in predicting patients’ prognosis. Therefore, this study aims to find potential therapeutic target genes and establish a gene signature for predicting the prognosis of LGG. CD44 is a marker of tumor stem cells and has prognostic value in various tumors, but its role in LGG is unclear. By analyzing three glioma datasets from Gene Expression Omnibus (GEO) database, CD44 was upregulated in LGG. We screened 10 CD44-related genes via protein–protein interaction (PPI) network; function enrichment analysis demonstrated that these genes were associated with biological processes and signaling pathways of the tumor; survival analysis showed that four genes (CD44, HYAL2, SPP1, MMP2) were associated with the overall survival (OS) and disease-free survival (DFS)of LGG; a novel four-gene signature was constructed. The prediction model showed good predictive value over 2-, 5-, 8-, and 10-year survival probability in both the development and validation sets. The risk score effectively divided patients into high- and low- risk groups with a distinct outcome. Multivariate analysis confirmed that the risk score and status of IDH were independent prognostic predictors of LGG. Among three LGG subgroups based on the presence of molecular parameters, IDH-mutant gliomas have a favorable OS, especially if combined with 1p/19q codeletion, which further confirmed the distinct biological pattern between three LGG subgroups, and the gene signature is able to divide LGG patients with the same IDH status into high- and low- risk groups. The high-risk group possessed a higher expression of immune checkpoints and was related to the activation of immunosuppressive pathways. Finally, this study provided a convenient tool for predicting patient survival. In summary, the four prognostic genes may be therapeutic targets and prognostic predictors for LGG; this four-gene signature has good prognostic prediction ability and can effectively distinguish high- and low-risk patients. High-risk patients are associated with higher immune checkpoint expression and activation of the immunosuppressive pathway, providing help for screening immunotherapy-sensitive patients.

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The suppressive role of HYAL1 and HYAL2 in the metastasis of colorectal cancer

Cited by 20 publications

References 31 publications

Dihydromethysticin, a natural molecule from Kava, suppresses the growth of colorectal cancer via the NLRC3/PI3K pathway

Dihydromethysticin, a natural molecule from Kava, suppresses the growth of colorectal cancer via the NLRC3/PI3K pathway

Comprehensive analysis of expression, prognosis and immune infiltration for TIMPs in glioblastoma

A Novel Four-Gene Signature Associated With Immune Checkpoint for Predicting Prognosis in Lower-Grade Glioma

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