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There is an interconnected network between S1P/sphingosine‐1‐phosphate receptor 1 (S1PR1), IL‐6/glycoprotein 130 (GP130), and signal transducer and activator of transcription 3 (STAT3) signaling pathways in the tumor microenvironment, which leads to cancer progression. S1P/S1PR1 and IL‐6/GP130 signaling pathways phosphorylate and activate STAT3, and it then induces the expression of S1PR1 and interleukin‐6 (IL‐6) in a positive feedback loop leading to cancer progression. We hypothesized that blockade of this amplification loop can suppress the growth and development of cancer cells. Therefore, we silenced STAT3 upstream molecules including the S1PR1 and GP130 molecules in cancer cells using small interfering RNA (siRNA)‐loaded alginate‐conjugated trimethyl chitosan (ATMC) nanoparticles (NPs). The generated NPs had competent properties including the appropriate size, zeta potential, polydispersity index, morphology, high uptake of siRNA, high rate of capacity, high stability, and low toxicity. We evaluated the effects of siRNA loaded ATMC NPs on tumor hallmarks of three murine‐derived cancer cell lines, including 4T1 (breast cancer), B16‐F10 (melanoma), and CT26 (colon cancer). The results confirmed the tumor‐suppressive effects of combinational targeting of S1PR1 and GP130. Moreover, combination therapy could potently suppress tumor growth as assessed by the chick chorioallantoic membrane assay. In this study, we targeted this positive feedback loop for the first time and applied this novel combination therapy, which provides a promising approach for cancer treatment. The development of a potent nanocarrier system with ATMC for this combination was also another aspect of this study, which should be further investigated in cancer animal models in further studies. [ABSTRACT FROM AUTHOR]

Background. MicroRNAs (miRNAs) are small non-coding RNAs which have been considered as major players in the process of carcinogenesis and drug responsiveness of breast cancer. Objectives. In this study, we aimed to investigate the expression pattern of let-7a and miR-205 tumorsuppressor miRNAs in breast cancer cell lines under treatment with paclitaxel. Material and methods. The half maximal inhibitory concentration (IC50) of paclitaxel was determined for 4 breast cancer cell lines, including MCF-7, MDA-MB-231, SKBR-3, and BT-474 by an MTT assay. The expression level of let-7a and miR-205, and their targets, K-RAS and HER3, was determined before and after treatment with paclitaxel, using quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR). Results. After treatment, the expression level of both let-7a and miR-205 was significantly increased in HER2- overexpressing cell line BT-474 (26.4- and 7.2-fold, respectively). In contrast, the HER2-negative cell lines MCF-7 and MDA-MB-231 showed a significantly decreased expression of both let-7a (30.3- and 13.5-fold, respectively) and miR-205 (20- and 18.1-fold, respectively). Controversially, SKBR-3 revealed a significantly decreased expression of both let-7a (1.3-fold) and miR-205 (1.3-fold). The expression level of K-RAS as a target of let-7a decreased in all cell lines significantly, but the pattern of alteration in the expression level of HER3 as a target of miR-205 in all cell lines was the reverse of the pattern of alteration in the expression level of miR-205. Conclusions. Our results confirmed a better response of HER2-overexpressing breast cancer to paclitaxel at the miRNA level. One putative reason could be the upregulation of tumor-suppressor miRNAs after treatment with paclitaxel. On the other hand, HER2-negative breast cancer cell lines showed a significantly decreased expression of tumor-suppressor miRNAs, a putative mechanism of resisting the therapy. [ABSTRACT FROM AUTHOR]

Introduction: MicroRNAs (miRNAs) are short non-coding single-stranded RNAs. Involving in post-transcriptional gene silencing, miRNAs are thought to play important roles in many cancers such as breast cancer. Paclitaxel is used widely in the treatment of breast cancer. In this study, we investigated the effect of paclitaxel treatment on the expression levels of two oncomirs (oncomiRs), miR-21 and miR-203, in breast cancer cell lines. Materials and methods: MTT assay was performed to determine IC50 of paclitaxel for human breast cancer cell lines including MCF-7, MDA-MB-231, SKBR3 and BT-474. After RNA extraction and cDNA synthesis, the expression levels of miRNAs were then quantitatively evaluated using real-time PCR. Results: Our results showed that after treatment, the expression levels of both miR-21 and miR-203 were significantly increased in HER2-positive cell lines, BT-474 and SKBR3. HER2-negative cell lines, MCF-7 and MDA-MB-231, in contrast had significantly decreased expression of both assessed oncomiRs. Conclusion: Our results showed that the expression levels of oncomiRs were increased in HER-2 positive breast cancer cells and this finding is in line with previous studies. Our findings present a probable mechanism of resistance against paclitaxel chemotherapy in HER2-positive breast cancers. [ABSTRACT FROM AUTHOR]

The immunosuppressive nature of the tumor microenvironment is a critical problem that should be considered before the design of immunotherapies. Interleukin (IL)-6 and its related downstream molecules such as signal transducer and activator of transcription (STAT)3 play an important role in the cancer progression, which can be considered as potential therapeutic targets. In the present study, we generated the active-targeted hyaluronate (HA) recoated N , N , N -trimethyl chitosan (TMC) nanoparticles (NPs) to deliver IL-6- and STAT3-specific small interfering RNAs (siRNAs) to the CD44-expressing cancer cells. We utilized the interaction between HA and CD44 to increase the specificity and efficacy of cellular uptake in NPs. The results showed that the synthesized NPs had efficient physicochemical characteristics, high transfection efficiency, low toxicity, and controlled siRNA release. siRNA-loaded NPs significantly inhibited the IL-6/STAT3 expression, which was associated with blockade of proliferation, colony formation, migration, and angiogenesis in cancer cells. These findings imply the potential of HA-TMC NPs as potent vectors in gene therapy and their application for the silencing of IL-6 and STAT3, as a novel anti-cancer combination therapeutic strategy, for the first time. • Hyaluronate recoating of trimethyl chitosan increased cellular uptake and stability of them. • IL-6- and STAT3-siRNA loaded HA-TMC NPs effectively downregulate IL-6/STAT3 axis. • IL-6/STAT3 axis silencing significantly inhibited cancer cells progression and development. [ABSTRACT FROM AUTHOR]