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21 pages, 3702 KiB

Open AccessArticle

Primary Colorectal Tumor Displays Differential Genomic Expression Profiles Associated with Hepatic and Peritoneal Metastases

by Maximiliano Gelli, Christophe Desterke, Mohamed Amine Bani, Valérie Boige, Charles Ferté, Peggy Dartigues, Bastien Job, Geraldine Perkins, Pierre Laurent-Puig, Diane Goéré, Jacques R. R. Mathieu, Jerome Cartry, Michel Ducreux and Fanny Jaulin

Cancers 2023, 15(17), 4418; https://doi.org/10.3390/cancers15174418 - 4 Sep 2023

Cited by 1 | Viewed by 1804

Abstract

Background: Despite improvements in characterization of CRC heterogeneity, appropriate risk stratification tools are still lacking in clinical practice. This study aimed to elucidate the primary tumor transcriptomic signatures associated with distinct metastatic routes. Methods: Primary tumor specimens obtained from CRC patients with either [...] Read more.

Background: Despite improvements in characterization of CRC heterogeneity, appropriate risk stratification tools are still lacking in clinical practice. This study aimed to elucidate the primary tumor transcriptomic signatures associated with distinct metastatic routes. Methods: Primary tumor specimens obtained from CRC patients with either isolated LM (CRC-Liver) or PM (CRC-Peritoneum) were analyzed by transcriptomic mRNA sequencing, gene set enrichment analyses (GSEA) and immunohistochemistry. We further assessed the clinico-pathological associations and prognostic value of our signature in the COAD-TCGA independent cohort. Results: We identified a significantly different distribution of Consensus Molecular Subtypes between CRC-Liver and CRC-peritoneum groups. A transcriptomic signature based on 61 genes discriminated between liver and peritoneal metastatic routes. GSEA showed a higher expression of immune response and epithelial invasion pathways in CRC-Peritoneum samples and activation of proliferation and metabolic pathways in CRC-Liver samples. The biological relevance of RNA-Seq results was validated by the immunohistochemical expression of three significantly differentially expressed genes (ACE2, CLDN18 and DUSP4) in our signature. In silico analysis of the COAD-TCGA showed that the CRC-Peritoneum signature was associated with negative prognostic factors and poor overall and disease-free survivals. Conclusions: CRC primary tumors spreading to the liver and peritoneum display significantly different transcriptomic profiles. The implementation of this signature in clinical practice could contribute to identify new therapeutic targets for stage IV CRC and to define individualized follow-up programs in stage II-III CRC. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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15 pages, 4850 KiB

Open AccessArticle

Plasma Exosome Proteins ILK1 and CD14 Correlated with Organ-Specific Metastasis in Advanced Gastric Cancer Patients

by Chenfei Zhou, Changting Qiao, Jun Ji, Wenqi Xi, Jinling Jiang, Liting Guo, Junwei Wu, Feng Qi, Qu Cai, Steven W. M. Olde Damink and Jun Zhang

Cancers 2023, 15(15), 3986; https://doi.org/10.3390/cancers15153986 - 5 Aug 2023

Cited by 1 | Viewed by 2107

Abstract

The exosome plays important roles in driving tumor metastasis, while the role of exosome proteins during organ-specific metastasis in gastric cancer has not been fully understood. To address this question, peripheral blood samples from 12 AGC patients with organ-specific metastasis, including distant lymphatic, [...] Read more.

The exosome plays important roles in driving tumor metastasis, while the role of exosome proteins during organ-specific metastasis in gastric cancer has not been fully understood. To address this question, peripheral blood samples from 12 AGC patients with organ-specific metastasis, including distant lymphatic, hepatic and peritoneal metastasis, were collected to purify exosomes and to detect exosome proteins by Nano-HPLC–MS/MS. Gastric cancer cell lines were used for in vitro experiments. Peripheral blood sample and ascites sample from one patient were further analyzed by single-cell RNA sequencing. GO and KEGG enrichment analysis showed different expression proteins of hepatic metastasis were correlated with lipid metabolism. For peritoneal metastasis, actin cytoskeleton regulation and glycolysis/gluconeogenesis could be enriched. ILK1 and CD14 were correlated with hepatic and peritoneal metastasis, respectively. Overexpression of CD14 and ILK1 impacted the colony formation ability of gastric cancer and increased expression of Vimentin. CD14 derived from immune cells in malignant ascites correlated with high activation of chemokine- and cytokine-mediated signaling pathways. In summary, biological functions of plasma exosome proteins among AGC patients with different metastatic modes were distinct, in which ILK1 and CD14 were correlated with organ-specific metastasis. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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17 pages, 12037 KiB

Open AccessArticle

Identification of MYEOV-Associated Gene Network as a Potential Therapeutic Target in Pancreatic Cancer

by Yu Chen, Jialun Wang, Qiyuan Guo, Xihan Li and Xiaoping Zou

Cancers 2022, 14(21), 5439; https://doi.org/10.3390/cancers14215439 - 4 Nov 2022

Cited by 1 | Viewed by 1842

Abstract

The molecular mechanism that promotes pancreatic cancer remains unclear, so it is important to find the molecular network of important genes related to pancreatic cancer. To find the key molecule of pancreatic cancer, differential gene expression analyses were analyzed by the Deseq2 package, [...] Read more.

The molecular mechanism that promotes pancreatic cancer remains unclear, so it is important to find the molecular network of important genes related to pancreatic cancer. To find the key molecule of pancreatic cancer, differential gene expression analyses were analyzed by the Deseq2 package, edgeR package, and limma-voom package, respectively. Pancreatic cancer survival-related genes were analyzed by COX survival analysis. Finally, we integrated the results to obtain the significantly differentially expressed gene, MYEOV (myeloma overexpressed gene), most strongly related to survival in pancreatic cancer. Experimental verification by qRT-PCR confirmed that transcription levels of MYEOV mRNA markedly increased in pancreatic cancer cells relative to normal human pancreatic ductal epithelial cells (HPDE). Through the comprehensive analysis of multiple databases, we constructed a molecular network centered on MYEOV and found specific links between molecules in this network and tumor-associated immune cells. It was noted that MYEOV could serve as a ceRNA by producing molecular sponging effects on hsa-miR-103a-3p and hsa-miR-107, thus affecting the role of GPRC5A, SERPINB5, EGFR, KRAS, EIF4G2, and PDCD4 on pancreatic cancer progression. Besides, we also identified that infiltrated immune cells are potential mediators for the molecules in the MYEOV-related network to promote pancreatic cancer progression. It is the first report to focus on the possibility that MYEOV may act as a competing endogenous RNA (ceRNA) to form an interactive network with some pancreatic cancer-related genes such as KRAS and serve as a key therapeutic target of pancreatic cancer treatment. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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16 pages, 2902 KiB

Open AccessArticle

m⁶A Methyltransferase KIAA1429 Regulates the Cisplatin Sensitivity of Gastric Cancer Cells via Stabilizing FOXM1 mRNA

by Zhongcheng Zhu, Yuan Zhou, Yongheng Chen, Zhongyi Zhou, Wenxue Liu, Linyi Zheng, Qian Pei, Fengbo Tan, Haiping Pei and Yuqiang Li

Cancers 2022, 14(20), 5025; https://doi.org/10.3390/cancers14205025 - 14 Oct 2022

Cited by 15 | Viewed by 2020

Abstract

Although cisplatin is frequently used to treat gastric cancer, the resistance is the main obstacle for effective treatment. mRNA modification, N6-methyladenosine (m⁶A), is involved in the tumorigenesis of many types of cancer. As one of the largest m⁶A methyltransferase [...] Read more.

Although cisplatin is frequently used to treat gastric cancer, the resistance is the main obstacle for effective treatment. mRNA modification, N6-methyladenosine (m⁶A), is involved in the tumorigenesis of many types of cancer. As one of the largest m⁶A methyltransferase complex components, KIAA1429 bridges the catalytic m⁶A methyltransferase components, such as METTL3. In gastric cancer, KIAA1429 was reported to promote cell proliferation. However, whether KIAA1429 is involved in the resistance of gastric cancer to cisplatin remains unclear. Here, we generated cisplatin resistant gastric cancer cell lines, and compared the m⁶A content between resistant cells and wild type cells. The m⁶A content as well as KIAA1429 expression are higher in resistant cells. Interestingly, the expression of KIAA1429 was significantly increased after cisplatin treatment. We then used shRNA to knockdown KIAA1429 and found that resistant cells responded more to cisplatin treatment after KIAA1429 depletion, while overexpression of KIAA1429 decreased the sensitivity. Moreover, we identified a putative p65 binding site on the promoter area of KIAA1429 and ChIP assay confirmed the binding. p65 depletion decreased the expression of KIAA1429. YTHDF1 is the most abundant m⁶A “reader” that interacts with m⁶A modified mRNA. Mechanistically, YTHDF1 was recruited to the 3′-untranslated Region (3′-UTR) of transcriptional factor, FOXM1 by KIAA1429 and stabilized FOXM1 mRNA. More importantly, KIAA1429 knockdown increased the sensitivity of resistant cells to cisplatin in vivo. In conclusion, our results demonstrated that KIAA1429 facilitated cisplatin resistance by stabilizing FOXM1 mRNA in gastric cancer cells. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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20 pages, 7305 KiB

Open AccessArticle

LINC01526 Promotes Proliferation and Metastasis of Gastric Cancer by Interacting with TARBP2 to Induce GNG7 mRNA Decay

by Jin-Yong Zhou, Jin-Yan Liu, Yu Tao, Chen Chen and Shen-Lin Liu

Cancers 2022, 14(19), 4940; https://doi.org/10.3390/cancers14194940 - 9 Oct 2022

Cited by 5 | Viewed by 1914

Abstract

Gastric cancer is the most common malignancy of the human digestive system. Long noncoding RNAs (lncRNAs) influence the occurrence and development of gastric cancer in multiple ways. However, the function and mechanism of LINC01526 in gastric cancer remain unknown. Herein, we investigated the [...] Read more.

Gastric cancer is the most common malignancy of the human digestive system. Long noncoding RNAs (lncRNAs) influence the occurrence and development of gastric cancer in multiple ways. However, the function and mechanism of LINC01526 in gastric cancer remain unknown. Herein, we investigated the function of LINC01526 with respect to the malignant progression of gastric cancer. We found that LINC01526 was upregulated in gastric cancer cells and tissues. The function experiments in vitro and the Xenograft mouse model in vivo proved that LINC01526 could promote gastric cancer cell proliferation and migration. Furthermore, LINC01526 interacted with TAR (HIV-1) RNA-binding protein 2 (TARBP2) and decreased the mRNA stability of G protein gamma 7 (GNG7) through TARBP2. Finally, the rescue assay showed that downregulating GNG7 partially rescued the cell proliferation inhibited by LINC01526 or TARBP2 silencing. In summary, LINC01526 promoted gastric cancer progression by interacting with TARBP2, which subsequently degraded GNG7 mRNA. This study not only explores the role of LINC01526 in gastric cancer, but also provides a laboratory basis for its use as a new biomarker for diagnosis and therapeutic targets. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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21 pages, 4642 KiB

Open AccessArticle

A LETM2-Regulated PI3K-Akt Signaling Axis Reveals a Prognostic and Therapeutic Target in Pancreatic Cancer

by Shurui Zhou, Ziyi Zhong, Yanzong Lu, Yunlong Li, Hanming Yao, Yue Zhao, Tairan Guo, Kege Yang, Yaqing Li, Shaojie Chen, Kaihong Huang and Guoda Lian

Cancers 2022, 14(19), 4722; https://doi.org/10.3390/cancers14194722 - 28 Sep 2022

Cited by 5 | Viewed by 1868

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the highest mortalities malignant tumors, which is characterized by difficult diagnosis, rapid progression and high recurrence rate. Nevertheless, PDAC responds poorly to conventional therapies, which highlights the urgency to identify novel prognostic and therapeutic targets. LEMT2 [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the highest mortalities malignant tumors, which is characterized by difficult diagnosis, rapid progression and high recurrence rate. Nevertheless, PDAC responds poorly to conventional therapies, which highlights the urgency to identify novel prognostic and therapeutic targets. LEMT2 was a newly discovered protein-encoding gene with little cancer research and an unclear mechanism. Thus, this study aimed to illustrate LETM2 as the crucial oncogene for tumor progression in PDAC. In this study, we analyzed the expression level and prognostic value of LETM2 in multiple cancers using pan-cancer analysis. The analyses based on the TCGA-GTEx dataset indicated that the LETM2 expression was obviously elevated in several cancers, and it was the most significantly related to the dismal prognosis of PDAC. Subsequently, we demonstrated the functional role and mechanism of LETM2 by clinical sample evaluation, and in in vitro and in vivo experiments. Immunohistochemical analyses showed that high expression of LETM2 was correlated with poor outcomes of PDAC. Moreover, we demonstrated that LETM2 knockdown significantly inhibited tumor proliferation and metastasis, and promoted cell apoptosis, while LETM2 overexpression exerted the opposite effects. Finally, the impairment caused by LETM2-knockdown could be recovered via excitation of the PI3k-Akt pathway in vitro and in vivo animal models, which suggested that LETM2 could activate the downstream PI3K-Akt pathway to participate in PDAC progression. In conclusion, the study enhanced our understanding of LETM2 as an oncogene hallmark of PDAC. LETM2 may facilitate tumor progression by activating the PI3K-Akt signaling pathway, which provides potential targets for the diagnosis, treatment, and prognosis of pancreatic cancer. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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16 pages, 4710 KiB

Open AccessArticle

Identification of Essential Tumor-Infiltrating Immune Cells and Relevant Genes in Left-Sided and Right-Sided Colon Cancers

by Chen Su, Zeyang Lin, Yongmei Cui, Jian-Chun Cai and Jingjing Hou

Cancers 2022, 14(19), 4713; https://doi.org/10.3390/cancers14194713 - 28 Sep 2022

Cited by 5 | Viewed by 2166

Abstract

Backgrounds: Colorectal cancer is the third most prevalent cancer worldwide. A right-sided colon cancer patient typically has a worse prognosis than one who has a left-sided colon cancer. There is an unclear understanding of how left-sided colon cancer differs from right-sided colon cancer [...] Read more.

Backgrounds: Colorectal cancer is the third most prevalent cancer worldwide. A right-sided colon cancer patient typically has a worse prognosis than one who has a left-sided colon cancer. There is an unclear understanding of how left-sided colon cancer differs from right-sided colon cancer in tumor-infiltrating immune cells (TIICs) and relevant genes. Methods: The Cancer Genome Atlas provided RNA-seq data and clinical information regarding colon adenocarcinoma. We conducted a single-sample gene set enrichment analysis (ssGSEA) to quantify the level of 24 immune cells infiltrating the tissues. Based on an analysis of univariate Cox regression, immune cell types associated with survival were identified. Weighted gene co-expression network analysis (WGCNA) was used to identify hub genes related to location and critical immune cells. Based on the Search Tool for the Retrieval of Interacting Genes (STRING), interaction potential was predicted among the hub genes. Hub genes that influence outcomes through immune infiltration were identified using the least absolute shrinkage and selection operator (LASSO). Then, we used the TISIDB database (a repository portal for tumor–immune system interactions) to validate the correlation between hub genes and immune cell infiltration. Finally, immunohistochemical assays were conducted to determine the levels of proteins expressed by critical TIICs and cancer cells. Results: Colon cancers on the right side of the body had higher levels of myeloid-derived suppressor cells (MDSCs) than on the left side. There were three key genes: LCP1, ITGB2, and IKZF1. It was found that their expression was linked to poor prognosis and an increased level of MDSC infiltration. An immunohistochemical study confirmed these findings. Conclusions: There is a higher rate of MDSC infiltration in right-sided colon cancer when compared with left-sided colon cancer. COAD outcomes are associated with changes in MDSC infiltration, and therefore LCP1, ITGB2, and IKZF1 may be novel targets for immunotherapy. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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18 pages, 8395 KiB

Open AccessArticle

Integrative Analysis of Angiogenesis-Related Long Non-Coding RNA and Identification of a Six-DEARlncRNA Signature Associated with Prognosis and Therapeutic Response in Esophageal Squamous Cell Carcinoma

by Shasha Cao, Xiaomin Wang, Xiaohui Liu, Junkuo Li, Lijuan Duan, Zhaowei Gao, Shumin Lun, Yanju Zhu, Haijun Yang, Hao Zhang and Fuyou Zhou

Cancers 2022, 14(17), 4195; https://doi.org/10.3390/cancers14174195 - 30 Aug 2022

Cited by 3 | Viewed by 1929

Abstract

Esophageal squamous cell carcinoma (ESCC) is a lethal gastrointestinal malignancy worldwide. We aimed to identify an angiogenesis-related lncRNAs (ARlncRNAs) signature that could predict the prognosis in ESCC. The GSE53624 and GSE53622 datasets were derived from the GEO database. The differently expressed ARlncRNAs (DEARlncRNAs) [...] Read more.

Esophageal squamous cell carcinoma (ESCC) is a lethal gastrointestinal malignancy worldwide. We aimed to identify an angiogenesis-related lncRNAs (ARlncRNAs) signature that could predict the prognosis in ESCC. The GSE53624 and GSE53622 datasets were derived from the GEO database. The differently expressed ARlncRNAs (DEARlncRNAs) were retrieved by the weighted gene co-expression network analysis (WGCNA), differential expression analysis, and correlation analysis. Optimal lncRNA biomarkers were screened from the training set and the six-DEARlncRNA signature comprising AP000696.2, LINC01711, RP11-70C1.3, AP000487.5, AC011997.1, and RP11-225N10.1 could separate patients into high- and low-risk groups with markedly different survival. The validation of the reliability of the risk model was performed by the Kaplan-Meier test, ROC curves, and risk curves in the test set and validation set. Predictive independence analysis indicated that risk score is an independent prognostic biomarker for predicting the prognosis of ESCC patients. Subsequently, a ceRNA regulatory network and functional enrichment analysis were performed. The IC50 test revealed that patients in the high-risk group were resistant to Gefitinib and Lapatinib. Finally, the six DEARlncRNAs were detected by qRT-PCR. In conclusion, we demonstrated a novel ARlncRNA signature as an independent prognostic factor to distinguish the risk of ESCC patients and benefit the personalized clinical applications. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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9 pages, 1886 KiB

Open AccessArticle

Clinical Diagnosis of Gastric Cancer by High-Sensitivity THz Fiber-Based Fast-Scanning Near-Field Imaging

by Hua Chen, Juan Han, Shihua Ma, Xiao Li, Tianzhu Qiu and Xiaofeng Chen

Cancers 2022, 14(16), 3932; https://doi.org/10.3390/cancers14163932 - 15 Aug 2022

Cited by 5 | Viewed by 1636

Abstract

The distinguishable absorption contrast among healthy gastric tissues, carcinoma in situ and cancer tissues in the THz frequency range is one of the keys to realizing gastric cancer diagnosis by THz imaging. Based on microwave devices and a sub-wavelength fiber, we developed a [...] Read more.

The distinguishable absorption contrast among healthy gastric tissues, carcinoma in situ and cancer tissues in the THz frequency range is one of the keys to realizing gastric cancer diagnosis by THz imaging. Based on microwave devices and a sub-wavelength fiber, we developed a fast-scanning THz imaging system combined with the principle of surface plasmon resonance enhancement. This imaging system has a near-field λ/17 spatial resolution and imaging S/N ratio as high as 10⁸:1, and the image results are directly displayed within 1 min. We also successfully demonstrated the image diagnostic capability on sliced tissues from eight patients with gastric cancer. The results indicate that THz absorption images can not only clearly distinguish cancer tissue from healthy tissues but also accurately define the margins of cancer. Through a medical statistical study of 40 sliced tissues from 40 patients, we prove that THz imaging can be used as a standalone method to diagnose gastric cancer tissues with a diagnostic specificity and sensitivity of 100%. Compared with the H&E staining method, THz imaging diagnosis makes the automation of tissue-sampling pre-screening procedure possible and assists in quickly determining the boundary between cancerous and healthy tissues. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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15 pages, 3312 KiB

Open AccessArticle

Comprehensive Analysis of Genomic Alterations in Hepatoid Adenocarcinoma of the Stomach and Identification of Clinically Actionable Alterations

by Rongjie Zhao, Hongshen Li, Weiting Ge, Xiuming Zhu, Liang Zhu, Xiangbo Wan, Guanglan Wang, Hongming Pan, Jie Lu and Weidong Han

Cancers 2022, 14(16), 3849; https://doi.org/10.3390/cancers14163849 - 9 Aug 2022

Cited by 5 | Viewed by 2548

Abstract

Hepatoid adenocarcinoma of the stomach (HAS) is a rare malignancy with aggressive biological behavior. This study aimed to compare the genetic landscape of HAS with liver hepatocellular carcinoma (LIHC), gastric cancer (GC), and AFP-producing GC (AFPGC) and identify clinically actionable alterations. Thirty-eight cases [...] Read more.

Hepatoid adenocarcinoma of the stomach (HAS) is a rare malignancy with aggressive biological behavior. This study aimed to compare the genetic landscape of HAS with liver hepatocellular carcinoma (LIHC), gastric cancer (GC), and AFP-producing GC (AFPGC) and identify clinically actionable alterations. Thirty-eight cases of HAS were collected for whole-exome sequencing. Significantly mutated genes were identified. TP53 was the most frequently mutated gene (66%). Hypoxia, TNF-α/NFκB, mitotic spindle assembly, DNA repair, and p53 signaling pathways mutated frequently. Mutagenesis mechanisms in HAS were associated with spontaneous or enzymatic deamination of 5-methylcytosine to thymine and defective homologous recombination-related DNA damage repair. However, LIHC was characteristic of exposure to aflatoxin and aristolochic acid. The copy number variants (CNVs) in HAS was significantly different compared to LIHC, GC, and AFPGC. Aggressive behavior-related CNVs were identified, including local vascular invasion, advanced stages, and adverse prognosis. In 55.26% of HAS patients there existed at least one clinically actionable alteration, including ERBB2, FGFR1, CDK4, EGFR, MET, and MDM2 amplifications and BRCA1/2 mutations. MDM2 amplification with functional TP53 was detected in 5% of HAS patients, which was proved sensitive to MDM2 inhibitors. A total of 10.53% of HAS patients harbored TMB > 10 muts/Mb. These findings improve our understanding of the genomic features of HAS and provide potential therapeutic targets. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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19 pages, 3570 KiB

Open AccessArticle

Pan-Cancer Analysis Reveals SH3TC2 as an Oncogene for Colorectal Cancer and Promotes Tumorigenesis via the MAPK Pathway

by Chengzhi Huang, Hui Yi, Yue Zhou, Qing Zhang and Xueqing Yao

Cancers 2022, 14(15), 3735; https://doi.org/10.3390/cancers14153735 - 31 Jul 2022

Cited by 9 | Viewed by 3093

Abstract

SH3 domain and tetrapeptide repeat 2 (SH3TC2) is a protein-encoding gene and has previously been described as a critical signaling hub for neurological disorders. Although increasing evidence supports a vital role of SH3TC2 in the tumorigenesis of various kinds of cancer, no systematic [...] Read more.

SH3 domain and tetrapeptide repeat 2 (SH3TC2) is a protein-encoding gene and has previously been described as a critical signaling hub for neurological disorders. Although increasing evidence supports a vital role of SH3TC2 in the tumorigenesis of various kinds of cancer, no systematic analysis of SH3TC2 is available. The function and mechanism of SH3TC2 in other cancers remain unknown. Thus, this study aimed to analyze SH3TC2 in various kinds of cancer to find its tumorigenic role in one or more specific cancers. In the current study, we analyzed the expression level and prognostic value of SH3TC2 in different tumors in the TCGA-GTEx pan-cancer dataset. Subsequently, the prognostic role and mechanism of SH3TC2 in colorectal cancer (CRC) were further explored via clinical samples and in vitro and in vivo experiments. We observed differential expression of SH3TC2 in colon adenocarcinoma (COAD), acute myeloid leukemia (LAML), READ (rectum adenocarcinoma), SKCM (skin cutaneous melanoma), and TGCT (testicular germ cell tumors). Subsequently, SH3TC2 showed a significant effect on the clinical stage and prognostic value in CRC, LAML, and SKCM. Moreover, we found in the TCGA database and seven GEO datasets that SH3TC2 was significantly highly expressed in tumor tissue. Through enrichment analysis of SH3TC2 and its co-expressed genes, we found that SH3TC2 may play a role in the MAPK signaling pathway. Correlation analysis indicated that SH3TC2 was significantly associated with multiple key factors in the MAPK signaling pathway. Additionally, higher expression of SH3TC2 was found in tumor tissue in our cohort including 40 CRC patients. Overexpression of SH3TC2 may imply poor prognosis. Knockdown of SH3TC2 significantly inhibited tumor invasion, migration, and proliferation. More importantly, knockdown of SH3TC2 inhibited tumor growth in a CRC mouse model. The study preliminarily conducted a pan-cancer study of SH3TC2 and further explored the mechanism of SH3TC2 in CRC. Our research revealed that higher expression of SH3TC2 may promote CRC progression and invasion via the MAPK signaling pathway. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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11 pages, 1273 KiB

Open AccessArticle

LncRNA HOXC-AS1 Sponges miR-99a-3p and Upregulates MMP8, Ultimately Promoting Gastric Cancer

by Yue Jiang, Xiangpan Li, Yu Yang, Jiajun Luo, Xunshan Ren, Jingwen Yuan and Qiang Tong

Cancers 2022, 14(14), 3534; https://doi.org/10.3390/cancers14143534 - 20 Jul 2022

Cited by 4 | Viewed by 1858

Abstract

Gastric cancer (GC) is among the most lethal tumors worldwide. Long noncoding RNAs (lncRNAs) are reported to be critical during the occurrence and progression of malignancies. The HOXC cluster antisense RNA 1 (HOXC-AS1) has been suggested to participate in the genesis and development [...] Read more.

Gastric cancer (GC) is among the most lethal tumors worldwide. Long noncoding RNAs (lncRNAs) are reported to be critical during the occurrence and progression of malignancies. The HOXC cluster antisense RNA 1 (HOXC-AS1) has been suggested to participate in the genesis and development of GC. Therefore, we examined GC cells and tissues for the expression of HOXC-AS1 and correlated the expression levels with the disease specific survival of the patients, finding that HOXC-AS1 was overexpressed and probably had a tendency of leading to a poor prognosis. The Cell Counting Kit-8 assay and colony formation assay were then performed under knockdown of HOXC-AS1, revealing that cell proliferation of GC was distinctly decreased. Afterwards, miR-99a-3p was predicted to bind with HOXC-AS1 by DIANA tools. We carried out dual-luciferase reporter gene assays to identify the interaction between them. After knockdown of HOXC-AS1, miR-99a-3p was clearly overexpressed in GC cells. In addition, matrix metalloproteinase 8 (MMP8) was shown to be combined with miR-99a-3p using TargetScan. Similar experiments, along with western blot, were conducted to validate the correlation between miR-99a-3p and MMP8. Finally, rescue experiments for CCK-8 were completed, disclosing that HOXC-AS1 promoted cell progression of GC through sponging miR-99a-3p followed by subsequent upregulation of MMP8. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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16 pages, 7438 KiB

Open AccessArticle

High-Fat Diet Enhances the Liver Metastasis Potential of Colorectal Cancer through Microbiota Dysbiosis

by Yina Yu, Yangke Cai, Bin Yang, Siyuan Xie, Wenjuan Shen, Yaoyi Wu, Ziqi Sui, Jianting Cai, Chao Ni and Jun Ye

Cancers 2022, 14(11), 2573; https://doi.org/10.3390/cancers14112573 - 24 May 2022

Cited by 16 | Viewed by 3487

Abstract

Obesity, metabolic changes, and intestinal microbiota disruption significantly affect tumorigenesis and metastasis in colorectal cancer (CRC). However, the relationships among these factors remain poorly understood. In this study, we found that a high-fat diet (HFD) promoted gut barrier dysfunction and inflammation in the [...] Read more.

Obesity, metabolic changes, and intestinal microbiota disruption significantly affect tumorigenesis and metastasis in colorectal cancer (CRC). However, the relationships among these factors remain poorly understood. In this study, we found that a high-fat diet (HFD) promoted gut barrier dysfunction and inflammation in the colorectum and liver. We further investigated gut microbiota changes through 16S rRNA sequencing of faecal samples from HFD-fed rats and CRC hepatic metastasis patients and found an abundance of Desulfovibrio (DSV). DSV could also induce barrier dysfunction in the colorectum and inflammation in the colorectum and liver, suggesting that it contributes to the formation of a microenvironment conducive to CRC tumorigenesis and metastasis. These findings highlight that HFD-induced microbiota dysbiosis, especially DSV abundance, could promote CRC initiation and metastasis. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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19 pages, 3712 KiB

Open AccessArticle

Studies of the Efficacy of Low-Dose Apatinib Monotherapy as Third-Line Treatment in Patients with Metastatic Colorectal Cancer and Apatinib’s Novel Anticancer Effect by Inhibiting Tumor-Derived Exosome Secretion

by Lingying Zhao, Qiang Yu, Chunyi Gao, Jingzhou Xiang, Bowen Zheng, Yujie Feng, Runyang Li, Wenqing Zhang, Xiaoting Hong, Yan-yan Zhan, Li Xiao and Tianhui Hu

Cancers 2022, 14(10), 2492; https://doi.org/10.3390/cancers14102492 - 19 May 2022

Cited by 12 | Viewed by 2696

Abstract

Antiangiogenic therapy is an important treatment strategy for metastatic colorectal cancer (mCRC). We carried out a clinical study of low-dose apatinib (250 mg) monotherapy as a third-line treatment in patients with mCRC and assessed its efficacy and safety. It demonstrated that low-dose apatinib [...] Read more.

Antiangiogenic therapy is an important treatment strategy for metastatic colorectal cancer (mCRC). We carried out a clinical study of low-dose apatinib (250 mg) monotherapy as a third-line treatment in patients with mCRC and assessed its efficacy and safety. It demonstrated that low-dose apatinib had comparable survival outcomes, significantly improved the patient quality of life, and caused tolerable adverse reactions. To further investigate the underlying mechanism of the effects of apatinib in CRC besides angiogenesis, we performed RNA-seq, and our results suggested that apatinib may have other potential antitumor mechanisms in CRC through multiple pathways, including exosomes secretion. In RKO and HCT116 cells, apatinib significantly reduced exosomes secretion by targeting multivesicular body (MVB) transport. Further studies have indicated that apatinib not only promoted the degradation of MVBs via the regulation of LAMP2 but also interfered with MVB transport by inhibiting Rab11 expression. Moreover, apatinib inhibited MVB membrane fusion by reducing SNAP23 and VAMP2 expression. In vivo, apatinib inhibited orthotopic murine colon cancer growth and metastasis and reduced the serum exosomes amount. This novel regulatory mechanism provides a new perspective for the antitumor effect of apatinib beyond angiogenesis inhibition. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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16 pages, 6590 KiB

Open AccessArticle

Targeting PELP1 Attenuates Angiogenesis and Enhances Chemotherapy Efficiency in Colorectal Cancer

by Jianlin Zhu, Lu Wang, Fan Liu, Jinghua Pan, Zhimeng Yao, Yusheng Lin, Yabing Yang, Xiao Xiong, Kai Li, Yi Yang, Yiran Zhang, Xiaodong Chu, Yunlong Pan and Hao Zhang

Cancers 2022, 14(2), 383; https://doi.org/10.3390/cancers14020383 - 13 Jan 2022

Cited by 6 | Viewed by 2528

Abstract

Abnormal angiogenesis is one of the important hallmarks of colorectal cancer as well as other solid tumors. Optimally, anti-angiogenesis therapy could restrain malignant angiogenesis to control tumor expansion. PELP1 is as a scaffolding oncogenic protein in a variety of cancer types, but its [...] Read more.

Abnormal angiogenesis is one of the important hallmarks of colorectal cancer as well as other solid tumors. Optimally, anti-angiogenesis therapy could restrain malignant angiogenesis to control tumor expansion. PELP1 is as a scaffolding oncogenic protein in a variety of cancer types, but its involvement in angiogenesis is unknown. In this study, PELP1 was found to be abnormally upregulated and highly coincidental with increased MVD in CRC. Further, treatment with conditioned medium (CM) from PELP1 knockdown CRC cells remarkably arrested the function of human umbilical vein endothelial cells (HUVECs) compared to those treated with CM from wildtype cells. Mechanistically, the STAT3/VEGFA axis was found to mediate PELP1-induced angiogenetic phenotypes of HUVECs. Moreover, suppression of PELP1 reduced tumor growth and angiogenesis in vivo accompanied by inactivation of STAT3/VEGFA pathway. Notably, in vivo, PELP1 suppression could enhance the efficacy of chemotherapy, which is caused by the normalization of vessels. Collectively, our findings provide a preclinical proof of concept that targeting PELP1 to decrease STAT3/VEGFA-mediated angiogenesis and improve responses to chemotherapy due to normalization of vessels. Given the newly defined contribution to angiogenesis of PELP1, targeting PELP1 may be a potentially ideal therapeutic strategy for CRC as well as other solid tumors. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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23 pages, 4194 KiB

Open AccessReview

Research Progress for Targeting Deubiquitinases in Gastric Cancers

by Tao An, Yanting Lu, Zhaoqi Gong, Yongtao Wang, Chen Su, Guimei Tang and Jingjing Hou

Cancers 2022, 14(23), 5831; https://doi.org/10.3390/cancers14235831 - 26 Nov 2022

Cited by 2 | Viewed by 2025

Abstract

Gastric cancers (GCs) are malignant tumors with a high incidence that threaten global public health. Despite advances in GC diagnosis and treatment, the prognosis remains poor. Therefore, the mechanisms underlying GC progression need to be identified to develop prognostic biomarkers and therapeutic targets. [...] Read more.

Gastric cancers (GCs) are malignant tumors with a high incidence that threaten global public health. Despite advances in GC diagnosis and treatment, the prognosis remains poor. Therefore, the mechanisms underlying GC progression need to be identified to develop prognostic biomarkers and therapeutic targets. Ubiquitination, a post-translational modification that regulates the stability, activity, localization, and interactions of target proteins, can be reversed by deubiquitinases (DUBs), which can remove ubiquitin monomers or polymers from modified proteins. The dysfunction of DUBs has been closely linked to tumorigenesis in various cancer types, and targeting certain DUBs may provide a potential option for cancer therapy. Multiple DUBs have been demonstrated to function as oncogenes or tumor suppressors in GC. In this review, we summarize the DUBs involved in GC and their associated upstream regulation and downstream mechanisms and present the benefits of targeting DUBs for GC treatment, which could provide new insights for GC diagnosis and therapy. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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20 pages, 1724 KiB

Open AccessReview

Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies

by Nannan Wang, Yuepeng Cao, Chengshuai Si, Peng Shao, Guoqing Su, Ke Wang, Jun Bao and Liu Yang

Cancers 2022, 14(20), 5160; https://doi.org/10.3390/cancers14205160 - 21 Oct 2022

Cited by 10 | Viewed by 4624

Abstract

Despite recent improvements in the comprehensive therapy of malignancy, metastatic colorectal cancer (mCRC) continues to have a poor prognosis. Notably, 5% of mCRC cases harbor Erb-B2 receptor tyrosine kinase 2 (ERBB2) alterations. ERBB2, commonly referred to as human epidermal growth factor receptor 2, [...] Read more.

Despite recent improvements in the comprehensive therapy of malignancy, metastatic colorectal cancer (mCRC) continues to have a poor prognosis. Notably, 5% of mCRC cases harbor Erb-B2 receptor tyrosine kinase 2 (ERBB2) alterations. ERBB2, commonly referred to as human epidermal growth factor receptor 2, is a member of the human epidermal growth factor receptor family of protein tyrosine kinases. In addition to being a recognized therapeutic target in the treatment of gastric and breast malignancies, it is considered crucial in the management of CRC. In this review, we describe the molecular biology of ERBB2 from the perspective of biomarkers for mCRC-targeted therapy, including receptor structures, signaling pathways, gene alterations, and their detection methods. We also discuss the relationship between ERBB2 aberrations and the underlying mechanisms of resistance to anti-EGFR therapy and immunotherapy tolerance in these patients with a focus on novel targeted therapeutics and ongoing clinical trials. This may aid the development of a new standard of care in patients with ERBB2-positive mCRC. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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20 pages, 3120 KiB

Open AccessReview

Tumor-Associated Neutrophils in Colorectal Cancer Development, Progression and Immunotherapy

by Wei Zheng, Jingjing Wu, Yao Peng, Jing Sun, Pu Cheng and Qi Huang

Cancers 2022, 14(19), 4755; https://doi.org/10.3390/cancers14194755 - 29 Sep 2022

Cited by 28 | Viewed by 4497

Abstract

The colorectal-cancer (CRC) incidence rate and mortality have remained high for several years. In recent years, immune-checkpoint-inhibitor (ICI) therapy has rapidly developed. However, it is only effective in a few CRC patients with microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) CRC. How to improve the [...] Read more.

The colorectal-cancer (CRC) incidence rate and mortality have remained high for several years. In recent years, immune-checkpoint-inhibitor (ICI) therapy has rapidly developed. However, it is only effective in a few CRC patients with microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) CRC. How to improve the efficiency of ICI therapy in CRC patients with microsatellite stability (MSS) remains a huge obstacle. Tumor-associated neutrophils (TANs), which are similar to macrophages, also have N₁ and N₂ phenotypes. They can be recruited and polarized through different cytokines or chemokines, and then play an antitumor or tumor-promoting role. In CRC, we find that the prognostic significance of TANs is still controversial. In this review, we describe the antitumor regulation of TANs, and their mechanism of promoting tumor progression by boosting the transformation of inflammation into tumors, facilitating tumor-cell proliferation, metastasis and angiogenesis. The targeting of TANs combined with ICIs may be a new treatment model for CRC. Relevant animal experiments have shown good responses, and clinical trials have also been carried out in succession. TANs, as “assistants” of ICI treatment, may become the key to the success of CRC immunotherapy, although no significant results have been obtained. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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22 pages, 3430 KiB

Open AccessReview

p21-Activated Kinase: Role in Gastrointestinal Cancer and Beyond

by Xiaodong Li and Feng Li

Cancers 2022, 14(19), 4736; https://doi.org/10.3390/cancers14194736 - 28 Sep 2022

Cited by 7 | Viewed by 2267

Abstract

Gastrointestinal tumors are the most common tumors, and they are leading cause of cancer deaths worldwide, but their mechanisms are still unclear, which need to be clarified to discover therapeutic targets. p21-activating kinase (PAK), a serine/threonine kinase that is downstream of Rho GTPase, [...] Read more.

Gastrointestinal tumors are the most common tumors, and they are leading cause of cancer deaths worldwide, but their mechanisms are still unclear, which need to be clarified to discover therapeutic targets. p21-activating kinase (PAK), a serine/threonine kinase that is downstream of Rho GTPase, plays an important role in cellular signaling networks. According to the structural characteristics and activation mechanisms of them, PAKs are divided into two groups, both of which are involved in the biological processes that are critical to cells, including proliferation, migration, survival, transformation and metabolism. The biological functions of PAKs depend on a large number of interacting proteins and the signaling pathways they participate in. The role of PAKs in tumors is manifested in their abnormality and the consequential changes in the signaling pathways. Once they are overexpressed or overactivated, PAKs lead to tumorigenesis or a malignant phenotype, especially in tumor invasion and metastasis. Recently, the involvement of PAKs in cellular plasticity, stemness and the tumor microenvironment have attracted attention. Here, we summarize the biological characteristics and key signaling pathways of PAKs, and further analyze their mechanisms in gastrointestinal tumors and others, which will reveal new therapeutic targets and a theoretical basis for the clinical treatment of gastrointestinal cancer. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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17 pages, 1140 KiB

Open AccessReview

How Gut Microbiota Are Shaped by Pattern Recognition Receptors in Colitis and Colorectal Cancer

by Furong Qing, Tao Xie, Lu Xie, Tianfu Guo and Zhiping Liu

Cancers 2022, 14(15), 3821; https://doi.org/10.3390/cancers14153821 - 6 Aug 2022

Cited by 7 | Viewed by 2777

Abstract

Disorders of gut microbiota have been closely linked to the occurrence of various intestinal diseases including colitis and colorectal cancer (CRC). Specifically, the production of beneficial bacteria and intestinal metabolites may slow the development of some intestinal diseases. Recently, it has been proposed [...] Read more.

Disorders of gut microbiota have been closely linked to the occurrence of various intestinal diseases including colitis and colorectal cancer (CRC). Specifically, the production of beneficial bacteria and intestinal metabolites may slow the development of some intestinal diseases. Recently, it has been proposed that pattern recognition receptors (PRRs) not only recognize pathogens and initiate inflammatory signal transduction to induce immune responses but also influence the composition of intestinal microorganisms. However, the mechanisms through which PRRs regulate gut microbiota in the setting of colitis and CRC have rarely been systematically reviewed. Therefore, in this paper, we summarize recent advances in our understanding of how PRRs shape gut microbiota and how this influences the development of colitis and CRC. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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16 pages, 2235 KiB

Open AccessReview

Histone Demethylase JMJD2D: A Novel Player in Colorectal and Hepatocellular Cancers

by Qiang Chen, Kesong Peng, Pingli Mo and Chundong Yu

Cancers 2022, 14(12), 2841; https://doi.org/10.3390/cancers14122841 - 8 Jun 2022

Cited by 5 | Viewed by 3632

Abstract

Posttranslational modifications (PTMs) of histones are well-established contributors in a variety of biological functions, especially tumorigenesis. Histone demethylase JMJD2D (also known as KDM4D), a member of the JMJD2 subfamily, promotes gene transcription by antagonizing H3K9 methylation. JMJD2D is an epigenetic factor coordinating androgen [...] Read more.

Posttranslational modifications (PTMs) of histones are well-established contributors in a variety of biological functions, especially tumorigenesis. Histone demethylase JMJD2D (also known as KDM4D), a member of the JMJD2 subfamily, promotes gene transcription by antagonizing H3K9 methylation. JMJD2D is an epigenetic factor coordinating androgen receptor activation, DNA damage repair, DNA replication, and cell cycle regulation. Recently, the oncogenic role of JMJD2D in colorectal cancer (CRC) and hepatocellular cancer (HCC) has been recognized. JMJD2D serves as a coactivator of β-catenin, Gli1/2, HIF1α, STAT3, IRF1, TCF4, and NICD or an antagonist of p53 to promote the progression of CRC and HCC. In this review, we summarize the molecular mechanisms of JMJD2D in promoting the progression of CRC and HCC as well as the constructive role of its targeting inhibitors in suppressing tumorigenesis and synergistically enhancing the efficacy of anti-PD-1/PD-L1 immunotherapy. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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