Ovarian cancer is one of the most lethal gynecological malignancies, with a recurrence rate of 70–80%, particularly in patients diagnosed at advanced stages (stage III or IV), where the five-year survival rate falls below 30%. A key driver of this recurrence is the presence of cancer stem cells (CSCs), which exhibit resistance to chemotherapy and possess the capacity for self-renewal, plasticity, and tumor regeneration. The tumor microenvironment (TME) plays a crucial role in maintaining ovarian cancer stem cells (OCSCs) by providing nutrient and oxygen gradients, extracellular matrix (ECM) interactions, immune cell modulation, and support from cancer-associated fibroblasts (CAFs). CAFs secrete growth factors, cytokines, and ECM components that create a pro-tumorigenic niche, promoting CSC maintenance, invasion, and chemoresistance. Additionally, dysregulation of critical signaling pathways, including WNT, NOTCH, PI3K/AKT/mTOR, TGF-β, JAK/STAT, Hedgehog, NF-κB, and Hippo, supports CSC stemness, plasticity, maintenance, and adaptability, thereby increasing their survival and progression. Numerous inhibitors targeting these pathways have shown promise in preclinical studies. This review discusses the molecular mechanisms underlying CSC-mediated recurrence in ovarian cancer and highlights emerging therapeutic strategies. Particular emphasis is placed on the potential of combination therapies involving routine platinum or taxane based regimens with OCSC inhibitors to overcome chemoresistance, reduce recurrence rates, and improve survival outcomes for patients with advanced-stage ovarian cancer.

WNT and TGFβ signaling pathways play critical regulatory roles in cardiomyocyte fate determination and differentiation. MiRNAs are also known to regulate different biological processes and signaling pathways. Here, we intended to find candidate miRNAs that are involved in cardiac differentiation through regulation of WNT and TGFβ signaling pathways. Bioinformatics analysis suggested hsa-miR-335-3p and hsa-miR-335-5p as regulators of cardiac differentiation. Then, RT-qPCR, dual luciferase, TOP/FOP flash, and western blot analyses were done to confirm the hypothesis. Human embryonic stem cells (hESCs) were differentiated into beating cardiomyocytes, and these miRNAs showed significant expression during the differentiation process. Gain and loss of function of miR-335-3p and miR-335-5p resulted in BRACHYURY, GATA4, and NKX2-5 (cardiac differentiation markers) expression alteration during the course of hESC cardiac differentiation. The overexpression of miR-335-3p and miR-335-5p also led to upregulation of CNX43 and TNNT2 expression, respectively. Our results suggest that this might be mediated through enhancement of WNT and TGFβ signaling pathways. Overall, we show that miR-335-3p/5p upregulates cardiac mesoderm (BRACHYURY) and cardiac progenitor cell (GATA4 and NKX2-5) markers, which are potentially mediated through activation of WNT and TGFβ signaling pathways. Our findings suggest miR-335-3p/5p to be considered as a regulator of the cardiac differentiation process.

Breast cancer represents the most common malignancy in women worldwide and the ErbB/PI3K pathway has been found to play a crucial role in regulation of the cancer cell growth. MicroRNAs have been implicated in regulating diverse cellular pathways and therefore, understanding the link between the regulatory microRNAs and the ErbB/PI3K signaling pathway could potentially be helpful for breast cancer prevention and treatment. The aim of this study is to examine the regulatory effect of miR-326 on ErbB/PI3K signaling pathway in breast cancer development and progression. The results of qRT-PCR, RNA seq, and array data indicated that miR-326 was remarkably down-regulated in breast tumor tissues and correlated with poor survival outcome. Importantly, very low levels of miR-326 expression were found in aggressive breast cells compared to less-aggressive cell types. Mechanistically, a gene network including EGFR, ErbB2, ErbB3, AKT1, AKT2, and AKT3 targeted by miR-326, thereby providing suppression of ErbB/PI3K pathway, detected by RT-qPCR, and dual luciferase assay. In addition, Western blot analysis revealed that miR-326 upregulation decreased PI3K signaling activity by decreasing total AKT and p-AKT protein level in SKBR3 cell lines. Interestingly, up regulation of ErbB2 rescued the effect of miR-326 on miR-326 target genes. Further functional assays demonstrated that up regulation of miR-326 significantly suppressed cell growth as evidenced by cell cycle, cell cycle associated genes expression, colony formation and MTT assays and induced apoptosis, detected by Annexin V-PI. In addition, EMT markers RT-qPCR, scratch, and Transwell assays showed inhibited cellular migration and invasion following miR-326 upregulation. Altogether, our results revealed that miR-326 play a tumor-suppressive role in breast cancer through inhibiting ErbB/PI3K pathway and miR-326 may serve as a potential therapeutic target for the treatment of patients with breast cancer.