Oncometabolic Nuclear Reprogramming of Cancer Stemness

Background: CDK12 is a promising therapeutic target in breast cancer with an effective ability of maintaining cancer cell stemness. Objective: We aim to investigate the mechanism of CDK12 in maintaining breast cancer stemness. Methods: CDK12 expression level was accessed by using RT-qPCR and IHC. CDK12-altered breast cancer cell lines MDA-MB-231-shCDK12 and SkBr-3-CDK12 were then established. CCK8, colony formation assays, and xenograft model were used to value the effect of CDK12 on tumorigenicity. Transwell assay, mammosphere formation, FACS, and lung metastasis model in vivo were determined. Western blot further characterized the mechanism of CDK12 in breast cancer stemness through the c-myc/β-catenin pathway. Results: Our results showed a higher level of CDK12 exhibited in breast cancer samples. Tumor formation, cancer cell mobility, spheroid forming, and the epithelial-mesenchymal transition will be enhanced in the CDK12high group. In addition, CDK12 was associated with lung metastasis and maintained breast cancer cell stemness. CDK12high cancer cells presented higher tumorigenicity and a population of CD44+ subset compared with CDK12low cells. Our study demonstrated c-myc positively expressed with CDK12. The c-myc/β-catenin signaling was activated by CDK12, which is a potential mechanism to initiate breast cancer stem cell renewal and may serve as a potential biomarker of breast cancer prognosis. Conclusion: CDK12 overexpression promotes breast cancer tumorigenesis and maintains the stemness of breast cancer by activating c-myc/β-catenin signaling. Inhibiting CDK12 expression may become a potential therapy for breast cancer.

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Cancer stemness as a target for immunotherapy is shaped by pro-inflammatory stress.

Current Stem Cell Research & Therapy ◽

10.2174/1574888x15666200309145901 ◽

2020 ◽

Vol 15 ◽

Author(s):

Nese Unver

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Immune Cells ◽

Tumor Recurrence ◽

Inflammatory Factors ◽

Cancer Stemness ◽

Self Renewal ◽

Inflammatory Stress ◽

Factors Affecting

: Cancer stem cells represent a rare subpopulation of cancer cells carrying self-renewal and differentiation features in the multi-step tumorigenesis, tumor recurrence and metastasis. Pro-inflammatory stress is highly associated with cancer stemness via induction of cytokines, tumor-promoting immune cells and cancer stemness-related signaling pathways. This review summarizes the major pro-inflammatory factors affecting cancer stem cell characteristics and the critical immunotherapeutic strategies to eliminate cancer stem cells.

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A Role for the Inflammatory Mediators Cox-2 and Metalloproteinases in Cancer Stemness

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520615666150318100822 ◽

2015 ◽

Vol 15 (7) ◽

pp. 837-855 ◽

Cited By ~ 7

Author(s):

G.K. Chimal-Ramírez ◽

N.A. Espinoza-Sanchez ◽

E.M. Fuentes-Panana

Keyword(s):

Inflammatory Mediators ◽

Cancer Stemness ◽

Cox 2

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YAP1 overexpression contributes to the development of enzalutamide resistance by induction of cancer stemness and lipid metabolism in prostate cancer

Oncogene ◽

10.1038/s41388-021-01718-4 ◽

2021 ◽

Author(s):

Hsiu-Chi Lee ◽

Chien-Hui Ou ◽

Yun-Chen Huang ◽

Pei-Chi Hou ◽

Chad J. Creighton ◽

...

Keyword(s):

Prostate Cancer ◽

Lipid Metabolism ◽

Critical Issue ◽

Castration Resistant Prostate Cancer ◽

Cancer Stemness ◽

New Treatment ◽

Underlying Mechanisms ◽

Transcriptional Complex

AbstractMetastatic castration-resistant prostate cancer (mCRPC) is a malignant and lethal disease caused by relapse after androgen-deprivation (ADT) therapy. Since enzalutamide is innovated and approved by US FDA as a new treatment option for mCRPC patients, drug resistance for enzalutamide is a critical issue during clinical usage. Although several underlying mechanisms causing enzalutamide resistance were previously identified, most of them revealed that drug resistant cells are still highly addicted to androgen and AR functions. Due to the numerous physical functions of AR in men, innovated AR-independent therapy might alleviate enzalutamide resistance and prevent production of adverse side effects. Here, we have identified that yes-associated protein 1 (YAP1) is overexpressed in enzalutamide-resistant (EnzaR) cells. Furthermore, enzalutamide-induced YAP1 expression is mediated through the function of chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII) at the transcriptional and the post-transcriptional levels. Functional analyses reveal that YAP1 positively regulates numerous genes related to cancer stemness and lipid metabolism and interacts with COUP-TFII to form a transcriptional complex. More importantly, YAP1 inhibitor attenuates the growth and cancer stemness of EnzaR cells in vitro and in vivo. Finally, YAP1, COUP-TFII, and miR-21 are detected in the extracellular vesicles (EVs) isolated from EnzaR cells and sera of patients. In addition, treatment with EnzaR-EVs induces the abilities of cancer stemness, lipid metabolism and enzalutamide resistance in its parental cells. Taken together, these results suggest that YAP1 might be a crucial factor involved in the development of enzalutamide resistance and can be an alternative therapeutic target in prostate cancer.

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Regulatory T cells promote glioma cell stemness through TGF-β–NF-κB–IL6–STAT3 signaling

Cancer Immunology Immunotherapy ◽

10.1007/s00262-021-02872-0 ◽

2021 ◽

Cited By ~ 1

Author(s):

Shasha Liu ◽

Chaoqi Zhang ◽

Boqiao Wang ◽

Huanyu Zhang ◽

Guohui Qin ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Tumor Growth ◽

Xenograft Model ◽

Malignant Growth ◽

Cancer Stemness ◽

The Core ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Tumorigenic Potential

AbstractGlioma stem cells (GSCs) contribute to the malignant growth of glioma, but little is known about the interaction between GSCs and tumor microenvironment. Here, we found that intense infiltration of regulatory T cells (Tregs) facilitated the qualities of GSCs through TGF-β secretion that helped coordinately tumor growth. Mechanistic investigations indicated that TGF-β acted on cancer cells to induce the core cancer stem cell-related genes CD133, SOX2, NESTIN, MUSASHI1 and ALDH1A expression and spheres formation via NF-κB–IL6–STAT3 signaling pathway, resulting in the increased cancer stemness and tumorigenic potential. Furthermore, Tregs promoted glioma tumor growth, and this effect could be abrogated with blockade of IL6 receptor by tocilizumab which also demonstrated certain level of therapeutic efficacy in xenograft model. Additionally, expression levels of CD133, IL6 and TGF-β were found to serve as prognosis markers of glioma patients. Collectively, our findings reveal a new immune-associated mechanism underlying Tregs-induced GSCs. Moreover, efforts to target this network may be an effective strategy for treating glioma.

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B7-H4 induces epithelial–mesenchymal transition and promotes colorectal cancer stemness

Pathology - Research and Practice ◽

10.1016/j.prp.2020.153323 ◽

2021 ◽

pp. 153323

Author(s):

Ying Feng ◽

Zhaoting Yang ◽

Chengye Zhang ◽

Nan Che ◽

Xingzhe Liu ◽

...

Keyword(s):

Colorectal Cancer ◽

Epithelial Mesenchymal Transition ◽

Cancer Stemness ◽

Mesenchymal Transition

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Roles of microRNAs in Regulating Cancer Stemness in Head and Neck Cancers

Cancers ◽

10.3390/cancers13071742 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1742

Author(s):

Melysa Fitriana ◽

Wei-Lun Hwang ◽

Pak-Yue Chan ◽

Tai-Yuan Hsueh ◽

Tsai-Tsen Liao

Keyword(s):

Growth Factor ◽

Head And Neck ◽

Cancer Cells ◽

Signaling Pathways ◽

Epithelial To Mesenchymal Transition ◽

Survival Rates ◽

Growth Factor Receptor ◽

Cancer Stemness ◽

Mesenchymal Transition

Head and neck squamous cell carcinomas (HNSCCs) are epithelial malignancies with 5-year overall survival rates of approximately 40–50%. Emerging evidence indicates that a small population of cells in HNSCC patients, named cancer stem cells (CSCs), play vital roles in the processes of tumor initiation, progression, metastasis, immune evasion, chemo-/radioresistance, and recurrence. The acquisition of stem-like properties of cancer cells further provides cellular plasticity for stress adaptation and contributes to therapeutic resistance, resulting in a worse clinical outcome. Thus, targeting cancer stemness is fundamental for cancer treatment. MicroRNAs (miRNAs) are known to regulate stem cell features in the development and tissue regeneration through a miRNA–target interactive network. In HNSCCs, miRNAs act as tumor suppressors and/or oncogenes to modulate cancer stemness and therapeutic efficacy by regulating the CSC-specific tumor microenvironment (TME) and signaling pathways, such as epithelial-to-mesenchymal transition (EMT), Wnt/β-catenin signaling, and epidermal growth factor receptor (EGFR) or insulin-like growth factor 1 receptor (IGF1R) signaling pathways. Owing to a deeper understanding of disease-relevant miRNAs and advances in in vivo delivery systems, the administration of miRNA-based therapeutics is feasible and safe in humans, with encouraging efficacy results in early-phase clinical trials. In this review, we summarize the present findings to better understand the mechanical actions of miRNAs in maintaining CSCs and acquiring the stem-like features of cancer cells during HNSCC pathogenesis.

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