Transforming growth factor-β signaling: from tumor microenvironment to anticancer therapy

Chan, Max Kam-Kwan; Chan, Emily Lok-Yiu; Ji, Zoey Ze-Yuan; Chan, Alex Siu‐Wing; Li, Chunjie; Leung, Kam Tong; To, Ka‐Fai; Tang, Patrick Ming‐Kuen

doi:10.37349/etat.2023.00137

Cited by 14 publications

(5 citation statements)

References 201 publications

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“…Two of the most extensively studied pro-inflammatory cytokines within the SASP are IL-6 and IL-8 [ 34 ]. Moreover, both anticancer and pro-tumor roles of TGF-β in cancer are contradictory, heterogeneous and molecular background-dependent [ 36 ]. Given the pivotal function of TGF-β in senescence re-enforcement and cancer immune evasion, it was selected as another SASP factor in this study [ 34 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Metochalcone induces senescence-associated secretory phenotype via JAK2/STAT3 pathway in breast cancer

ZHOU,

WAN,

XIAO

et al. 2024

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Breast and lung cancers are the leading causes of mortality and most frequently diagnosed cancers in women and men, respectively, worldwide. Although the antitumor activity of chalcones has been extensively studied, the molecular mechanisms of isoliquiritigenin analog 2', 4', 4-trihydroxychalcone (metochalcone; TEC) against carcinomas remain less well understood. In this study, we found that TEC inhibited cell proliferation of breast cancer BT549 cells and lung cancer A549 cells in a concentration-dependent manner. TEC induced cell cycle arrest in the S-phase, cell migration inhibition in vitro , and reduced tumor growth in vivo . Moreover, transcriptomic analysis revealed that TEC modulated the activity of the JAK2/STAT3 and P53 pathways. TEC triggered the senescence-associated secretory phenotype (SASP) by repressing the JAK2/STAT3 axis. The mechanism of metochalcone against breast cancer depended on the induction of SASP via deactivation of the JAK2/STAT3 pathway, highlighting the potential of chalcone in senescence-inducing therapy against carcinomas.

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Section: Discussionmentioning

confidence: 99%

Metochalcone induces senescence-associated secretory phenotype via JAK2/STAT3 pathway in breast cancer

ZHOU,

WAN,

XIAO

et al. 2024

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“…TGF-β has intricate roles in tumors, often acting as a tumor suppressor in early stages, but its aberrant activation during tumor progression can promote occurrence, invasion, and metastasis ( 20 , 21 ). TGF-β promotes tumor progression through various mechanisms, including cell proliferation, epithelial-mesenchymal transition (EMT) regulation, immune evasion, and drug resistance ( 22 - 24 ). In this study, we discovered significant enrichment of TGF-β-related pathways in GO-BP and GSEA analyses, further supporting the significant correlation between HACE1 expression and the TGF-β signaling pathway, indicating HACE1’s likely crucial role in tumor development.…”

Section: Discussionmentioning

confidence: 99%

Unveiling the role of HACE1 in cervical cancer: implications for human papillomavirus infection and prognosis

Xiang,

Wang,

et al. 2024

Transl Cancer Res

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Background Cervical cancer, one of the prevalent malignancies among females, is closely associated with human papillomavirus (HPV) infection. Homologous to the E6-AP carboxyl terminus (HECT) domain and ankyrin repeat containing E3 ubiquitin-protein ligase 1 (HACE1) plays pivotal roles in various cancers. This study aimed to elucidate the expression of HACE1 in cervical cancer and its correlation with clinical features. Methods From The Cancer Genome Atlas Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA-CESC) and Gene Expression Omnibus (GEO, GSE6791) datasets, we obtained RNA-Seq profiles and associated clinical information. Differential gene analysis was conducted using the R “limma” package. Implications for HPV infection and the overall survival (OS) of cervical cancer were determined by performing differential expression analysis and the Cox proportional hazards regression model. Immunohistochemical analyses were used to validate the expression in cervical cancer and normal cervical tissue. Further, nomogram was constructed to predict OS in cervical cancer. Whether the model was credible was evaluated according to receiver operating characteristic (ROC) curves and concordance curves. To further evaluate the potential functions of HACE1, we conducted functional enrichment analysis. Finally, we assessed methylation levels in HPV+ and HPV− patients in the TCGA-CESC dataset. Results Utilizing TCGA and GSE6791 datasets, we observed significant upregulation of HACE1 in cervical cancer patients, particularly linked to HPV infection. Immunohistochemical staining revealed enhanced HACE1 expression in tumor tissues. Further analysis demonstrated a significant positive correlation between elevated HACE1 and HPV-associated proteins (E1, E6, and E7). Moreover, high HACE1 expression was associated with adverse prognosis in cervical cancer patients. Multivariate Cox analysis indicated that HACE1 could serve as an independent prognostic factor. We developed a prognostic model integrating HPV subtypes, the International Federation of Gynecology and Obstetrics (FIGO) staging, and HACE1, exhibiting strong predictive efficacy for cervical cancer prognosis. Gene enrichment analysis indicated HACE1’s potential involvement in multiple signaling pathways during cervical cancer progression, while the demethylation of cg03002526 in HPV-positive patients might contribute to HACE1 upregulation. Conclusions Our study reveals that HACE1 upregulation is associated with cervical cancer, particularly in HPV-positive patients. HACE1 emerges as an independent prognostic factor, linked to unfavorable outcomes.

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“…Alterations in oxidative phosphorylation not only promote ovarian cancer cell survival and proliferation, but also enable migration, acquisition of chemotherapy resistance, maintenance of a cancer stem cell phenotype, and evasion of anti-tumor immune defenses [1,40]. Furthermore, the TGF-β pathway has complex functions in tumor cells, whereby it acts as a tumor suppressor in the early stages of tumors and promotes tumor development in the later stages [41,42]. The TGF-β/SMAD pathway can influence tumor cell migration and invasion by regulating EMT (epithelialmesenchymal transition) [43,44].…”

Section: Discussionmentioning

confidence: 99%

Functional analysis and validation of oncodrive gene AP3S1 in ovarian cancer through filtering of mutation data from whole-exome sequencing

Kong,

Wu,

Liu

et al. 2024

Eur J Med Res

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Background High-grade serous ovarian carcinoma (HGSOC) is the most aggressive and prevalent subtype of ovarian cancer and accounts for a significant portion of ovarian cancer-related deaths worldwide. Despite advancements in cancer treatment, the overall survival rate for HGSOC patients remains low, thus highlighting the urgent need for a deeper understanding of the molecular mechanisms driving tumorigenesis and for identifying potential therapeutic targets. Whole-exome sequencing (WES) has emerged as a powerful tool for identifying somatic mutations and alterations across the entire exome, thus providing valuable insights into the genetic drivers and molecular pathways underlying cancer development and progression. Methods Via the analysis of whole-exome sequencing results of tumor samples from 90 ovarian cancer patients, we compared the mutational landscape of ovarian cancer patients with that of TCGA patients to identify similarities and differences. The sequencing data were subjected to bioinformatics analysis to explore tumor driver genes and their functional roles. Furthermore, we conducted basic medical experiments to validate the results obtained from the bioinformatics analysis. Results Whole-exome sequencing revealed the mutational profile of HGSOC, including BRCA1, BRCA2 and TP53 mutations. AP3S1 emerged as the most weighted tumor driver gene. Further analysis of AP3S1 mutations and expression demonstrated their associations with patient survival and the tumor immune response. AP3S1 knockdown experiments in ovarian cancer cells demonstrated its regulatory role in tumor cell migration and invasion through the TGF-β/SMAD pathway. Conclusion This comprehensive analysis of somatic mutations in HGSOC provides insight into potential therapeutic targets and molecular pathways for targeted interventions. AP3S1 was identified as being a key player in tumor immunity and prognosis, thus providing new perspectives for personalized treatment strategies. The findings of this study contribute to the understanding of HGSOC pathogenesis and provide a foundation for improved outcomes in patients with this aggressive disease.

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Transforming growth factor-β signaling: from tumor microenvironment to anticancer therapy

Cited by 14 publications

References 201 publications

Metochalcone induces senescence-associated secretory phenotype via JAK2/STAT3 pathway in breast cancer

Metochalcone induces senescence-associated secretory phenotype via JAK2/STAT3 pathway in breast cancer

Unveiling the role of HACE1 in cervical cancer: implications for human papillomavirus infection and prognosis

Functional analysis and validation of oncodrive gene AP3S1 in ovarian cancer through filtering of mutation data from whole-exome sequencing

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