Stemness in solid malignancies: coping with immune attack
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Porphyromonas gingivalis potentiates stem-like properties of oral squamous cell carcinoma by modulating SCD1-dependent lipid synthesis via NOD1/KLF5 axis
Cancer stem cells (CSCs) are widely acknowledged as primary mediators to the initiation and progression of tumors. The association between microbial infection and cancer stemness has garnered considerable scholarly interest in recent years. Porphyromonas gingivalis (P. gingivalis) is increasingly considered to be closely related to the development of oral squamous cell carcinoma (OSCC). Nevertheless, the role of P. gingivalis in the stemness of OSCC cells remains uncertain. Herein, we showed that P. gingivalis was positively correlated with CSC markers expression in human OSCC specimens, promoted the stemness and tumorigenicity of OSCC cells, and enhanced tumor formation in nude mice. Mechanistically, P. gingivalis increased lipid synthesis in OSCC cells by upregulating the expression of stearoyl-CoA desaturase 1 (SCD1) expression, a key enzyme involved in lipid metabolism, which ultimately resulted in enhanced acquisition of stemness. Moreover, SCD1 suppression attenuated P. gingivalis-induced stemness of OSCC cells, including CSCs markers expression, sphere formation ability, chemoresistance, and tumor growth, in OSCC cells both in vitro and in vivo. Additionally, upregulation of SCD1 in P. gingivalis-infected OSCC cells was associated with the expression of KLF5, and that was modulated by P. gingivalis-activated NOD1 signaling. Taken together, these findings highlight the importance of SCD1-dependent lipid synthesis in P. gingivalis-induced stemness acquisition in OSCC cells, suggest that the NOD1/KLF5 axis may play a key role in regulating SCD1 expression and provide a molecular basis for targeting SCD1 as a new option for attenuating OSCC cells stemness.
CD146 regulates the stemness and chemoresistance of hepatocellular carcinoma via JAG2-NOTCH signaling
CD146 plays a key role in cancer progression and metastasis. Cancer stem cells (CSCs) are responsible for tumor initiation, drug resistance, metastasis, and recurrence. In this study, we explored the role of CD146 in the regulation of liver CSCs. Here, we demonstrated that CD146 was highly expressed in liver CSCs. CD146 overexpression promoted the self-renewal ability and chemoresistance of Hepatocellular Carcinoma (HCC) cells in vitro and tumorigenicity in vivo. Inversely, knockdown of CD146 restrained these abilities. Mechanistically, CD146 activated the NF-κB signaling to up-regulate JAG2 expression and activated the Notch signaling, which resulted in increased stemness of HCC. Furthermore, JAG2 overexpression restored the Notch signaling activity, the stemness, and chemotherapeutic resistance caused by CD146 knockdown. These results demonstrated that CD146 positively regulates HCC stemness by activating the JAG2-NOTCH signaling. Combined targeting of CD146 and JAG2 may represent a novel therapeutic strategy for HCC treatment.
MiR-769-5p of macrophage exosomes induced by GRP78 promotes stemness and chemoresistance in colorectal cancer
The tumor microenvironment (TME) plays an important role in tumorigenesis and development. Tumor-associated macrophages (TAMs) are essential members of the TME, the exosomes and miRNAs they secrete are crucial in tumor regulation. Our previous study showed that GRP78-induced macrophages infinitely tend to be M2-type TAMs. In this study, the exosomes of M0 and GRP78-induced macrophage were collected and co-incubated with colorectal cancer (CRC) cells. The results implied that macrophage exosomes induced by GRP78 (GRP78-exos) significantly promoted stemness and chemoresistance in CRC in vitro and in vivo. Further, the top 5 miRNAs upregulated in GRP78-exos were obtained from miRNA sequencing data. The qRT-PCR validation revealed that miR-769-5p was the most observably upregulated and could be directly transferred into CRC cells via GRP78-exos. Mechanistically, the study indicated that miR-769-5p targeted MAPK1 to regulate the cell cycle-related proteins RB1, cyclin D1, and cyclin E1. This contributes to CRC cells entering a quiescent state, which leads to the development of chemoresistance. Moreover, miR-769-5p is also expressed higher in the tissues of 5-FU-resistant CRC patients. In summary, the findings indicate a novel function of miR-769-5p as a potential marker for the diagnosis and treatment of chemotherapy resistance in CRC.
Chromobox protein homolog 7 suppresses the stem-like phenotype of glioblastoma cells by regulating the myosin heavy chain 9-NF-κB signaling pathway
Cancer stem cells (CSCs) are significant factors in the treatment resistance and recurrence of glioblastoma. Chromobox protein homolog 7 (CBX7) can inhibit the progression of various tumors, but its impact on the stem cell-like properties of glioblastoma cells remains unclear. Clinically, low levels of CBX7 are associated with poor prognosis and increased distant metastasis in glioblastoma patients, and this low expression is caused by methylation of the CBX7 promoter. Our current research indicates that CBX7 plays a key role in suppressing the stem-like phenotype of glioblastoma. In this study, through bioinformatics analysis, we found that CBX7 is the most significantly downregulated member of the CBX family in glioblastoma and is closely associated with the stem-like phenotype of glioblastoma cells. We show that CBX7 promotes the degradation of myosin heavy chain 9 (MYH9) protein through the ubiquitin-proteasome pathway via the polycomb repressive complex 1 (PRC1) and suppresses the stem-like phenotype of glioblastoma cells by inhibiting the nuclear factor kappa-B (NF-κB) signaling pathway. Furthermore, overexpression of MYH9 in glioblastoma cells reverses the inhibitory effects of CBX7 on migration, proliferation, invasion, and stemness of glioblastoma cells. In summary, CBX7 acts as a tumor suppressor by inhibiting the stem cell-like characteristics of glioblastoma. The CBX7-MYH9-NF-κB signaling axis may serve as a potential therapeutic target for glioblastoma.
Dopamine in the tail of the striatum facilitates avoidance in threat–reward conflicts
Responding appropriately to potential threats before they materialize is critical to avoiding disastrous outcomes. Here we examine how threat-coping behavior is regulated by the tail of the striatum (TS) and its dopamine input. Mice were presented with a potential threat (a moving object) while pursuing rewards. Initially, the mice failed to obtain rewards but gradually improved in later trials. We found that dopamine in TS promoted avoidance of the threat, even at the expense of reward acquisition. Furthermore, the activity of dopamine D1 receptor-expressing neurons promoted threat avoidance and prediction. In contrast, D2 neurons suppressed threat avoidance and facilitated overcoming the potential threat. Dopamine axon activation in TS not only potentiated the responses of dopamine D1 receptor-expressing neurons to novel sensory stimuli but also boosted them acutely. These results demonstrate that an opponent interaction of D1 and D2 neurons in the TS, modulated by dopamine, dynamically regulates avoidance and overcoming potential threats.
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