Exosomal MicroRNA-325 Enhances Trophoblast Migration and Invasion Through Downregulation of Lethal-7b and Upregulation of Forkhead Box Protein O1 Expression in Preeclampsia

We aimed to explore the mechanism by how microRNA (miRNA)-325 derived from marrow mesenchymal stem cell exosomes (MSC-exos) affects the trophoblast progression in preeclampsia (PE). RT-qPCR detected the level of miRNA let-7b and FOXO1 in the placenta tissue of PE patients. Functional experiment was performed to analyze the effect of FOXO1 inhibitor and let-7b mimics on cell migration, invasion and apoptosis through Transwell assay and TUNEL staining. The trophoblast cell was co-cultured with overexpressed-miR-325 MSC-exos to measure gene expression and cell progression. let-7b was highly and FOXO1 was lowly expressed in PE placenta tissue. let-7b directly targeted and inhibited FOXO1 expression. Importantly, as miR-325 was internalized by trophoblast cells through MSC-exos, MSC-exos overexpressing miR-325 inhibited let-7b expression in trophoblasts, up-regulated FOXO1 and activated AKT signaling pathway. Further, MSC-exos treatment promoted invasion and migration of trophoblast cell and inhibited apoptosis. In conclusion, miR-325 derived from MSC-exos promotes the invasion and migration of trophoblast cells in PE through inhibition of let7b and upregulation of FOXO1.

Bone Marrow Mesenchymal Stem Cell (BMSC)-Derived Exosomal miR-168-5p Inhibits Proliferation and Chemotherapy Resistance in Gastric Cancer by Downregulation of Cyclin D1 and P Glycoprotein

miR-168-5p is indicated as an upstream effector of the tumor suppressor signal pathway in ovarian cancer and bladder cancer, but the role in gastric cancer (GC) remains unknown. This study aims to reveal the expression and significance of miR-168-5p in GC. RT-qPCR analysis was used to detect the expression of miR-168-5p in GC tissues and plasma, and the relationship of miR-168-5p and CCND1 was evaluated. GC cells were co-cultured with BMSCs or transfected with miR-168-5p mimic. CCK-8 assay and flow cytometry were conducted to assess the effect of miR-168-5p in GC and the interaction between BMSCs and cancer cell progression. Animal experiment was established to explore the in vivo effect of miR-168-5p. miR-168-5p is poorly expressed in gastric cancer cells and the plasma of patients with gastric cancer. BMSC co-culture is similar to miR-168-5p mimic induced miR-168-5p expression increase. miR-168-5p overexpression decreased the proliferative, invasive and migratory capacities of GC cells, and promoted apoptosis. Mechanically, miR-168-5p targeted and decreased the expression of CCND1. Additionally, the low miR-168-5p expression in GC was closely related to poor prognosis and malignant transformation. BMSC exosomes carrying miR-168-5p suppress cell progression in GC when inhibiting the expression of CCND1 and P glycoprotein, which indicates potential diagnostic and prognostic value of miR-168-5p and helps the development of miR-168-5p-based treatment for drug-resistant GC.

MiRNA-136-5p Sensitizes Liver Cancer Cells to Docetaxel by Targeting P53 and Enhances Cell Migration

We aimed to explore whether microRNA (miRNA)-136-5p modulates P53 expression, and affects the efficacy of docetaxel treatment for liver cancer. miRNA array screened the differentially expressed miRNAs in biopsy tissues of liver cancer patients, and the expression of miR-136-5p and P53 in tissues and cells by RT-PCR. Following docetaxel treatment, through increased- and decreased-function method, we detected the impact of the miRNA on cell progression, as well as the sensitivity of docetaxel through MTT assay and colony formation experiment. The correlation between miR-136-5p and P53 was evaluated. The expression of miR-136-5p in liver cancer cells is up-regulated, which is consistent with the results of bioinformatics analysis. Further, miR-136-5p overexpression promoted cell proliferation and migration, and sensitized liver cancer cells to docetaxel. Interestingly, P53 was indicated to bind to miR-136-5p, and P53 participated in the up-regulation of MMP10 induced by miR-136-5p. miR-136-5p enhances the sensitivity to docetaxel in liver cancer and thus could be a biomarker for the treatment against liver cancer.

Secretory Autophagy Forges a Therapy Resistant Microenvironment in Melanoma

Melanoma is the most aggressive skin cancer characterized by high mutational burden and large heterogeneity. Cancer cells are surrounded by a complex environment, critical to tumor establishment and progression. Thus, tumor-associated stromal components can sustain tumor demands or impair cancer cell progression. One way to manage such processes is through the regulation of autophagy, both in stromal and tumor cells. Autophagy is a catabolic mechanism that provides nutrients and energy, and it eliminates damaged organelles by degradation and recycling of cellular elements. Besides this primary function, autophagy plays multiple roles in the tumor microenvironment capable of affecting cell fate. Evidence demonstrates the existence of novel branches in the autophagy system related to cytoplasmic constituent’s secretion. Hence, autophagy-dependent secretion assembles a tangled network of signaling that potentially contributes to metabolism reprogramming, immune regulation, and tumor progression. Here, we summarize the current awareness regarding secretory autophagy and the intersection with exosome biogenesis and release in melanoma and their role in tumor resistance. In addition, we present and discuss data from public databases concerning autophagy and exosome-related genes as important mediators of melanoma behavior. Finally, we will present the main challenges in the field and strategies to translate most of the pre-clinical findings to clinical practice.

The Impact of Iron Chelators on the Biology of Cancer Stem Cells

Neoplastic diseases are still a major medical challenge, requiring a constant search for new therapeutic options. A serious problem of many cancers is resistance to anticancer drugs and disease progression in metastases or local recurrence. These characteristics of cancer cells may be related to the specific properties of cancer stem cells (CSC). CSCs are involved in inhibiting cells’ maturation, which is essential for maintaining their self-renewal capacity and pluripotency. They show increased expression of transcription factor proteins, which were defined as stemness-related markers. This group of proteins includes OCT4, SOX2, KLF4, Nanog, and SALL4. It has been noticed that the metabolism of cancer cells is changed, and the demand for iron is significantly increased. Iron chelators have been proven to have antitumor activity and influence the expression of stemness-related markers, thus reducing chemoresistance and the risk of tumor cell progression. This prompts further investigation of these agents as promising anticancer novel drugs. The article presents the characteristics of stemness markers and their influence on the development and course of neoplastic disease. Available iron chelators were also described, and their effects on cancer cells and expression of stemness-related markers were analyzed.

Hypoxia Activates Notch4 via ERK/JNK/P38 MAPK Signaling Pathways to Promote Lung Adenocarcinoma Progression and Metastasis

Hypoxia contributes to the progression and metastasis of lung adenocarcinoma (LUAD). However, the specific underlying molecular mechanisms have not been fully elucidated. Here we report that Notch4 is upregulated in lung tissue from lung cancer patients. Functionally, Hypoxia activates the expressions of Delta-like 4 and Notch4, resulting in the excessive proliferation and migration of LUAD cells as well as apoptotic resistance. Notch4 silencing reduced ERK, JNK, and P38 activation. Meanwhile, Notch4 overexpression enhanced ERK, JNK, and P38 activation in LUAD cells. Furthermore, Notch4 exerted pro-proliferation, anti-apoptosis and pro-migration effects on LUAD cells that were partly reversed by the inhibitors of ERK, JNK, and p38. The binding interaction between Notch4 and ERK/JNK/P38 were confirmed by the co-immunoprecipitation assay. In vivo study revealed that Notch4 played a key role in the growth and metastasis of LUAD using two xenograft models. This study demonstrates that hypoxia activates Notch4-ERK/JNK/P38 MAPK signaling pathways to promote LUAD cell progression and metastasis.