Inflammatory cells and mediators form a major part of the tumor microenvironment and play important roles in the regulation of cancer initiation, tumor cell proliferation, and metastasis. MicroRNAs (miRNAs) play important roles in several physiological and pathological processes, including the regulation of the inflammatory microenvironment in cancer. Transforming growth factor-β (TGF-β) is an inflammation-related cytokine that functions in both tumor suppression and promotion; however, its underlying molecular mechanisms remain unclear. Recent evidence indicates an association between miRNAs and TGF-β signaling, providing new insight into the nature of the inflammatory microenvironment in cancer. The present review is an overview of the interaction between miRNAs and inflammatory cytokines, with emphasis on the cross talk between TGF-β signaling and miRNAs and their influence on cancer cell behavior. The emerging roles of miRNAs in cancer-related inflammation and the potential to target miRNA signaling pathways for cancer therapy are also discussed.

Most chemotherapeutic drugs and their nanomedicine formulations exert anticancer activity by inducing cancer cell apoptosis. However, cancer cells inherently have and acquire many antiapoptosis mechanisms, causing cancer drug resistance and poor prognoses in patients. Herein, a potent paraptosis‐inducing nanomedicine is reported that causes quick nonapoptotic death of cancer cells, overcoming apoptosis‐based resistance and effectively inhibiting drug‐resistant tumor growth. The nanomedicine is composed of micelles made from an amphiphilic 8‐hydroxyquinoline (HQ)‐conjugate block copolymer with polyethylene glycol. Cu2+ can catalyze the hydrolysis of the HQ conjugation linker and liberate HQ, and these molecules can form the complex Cu(HQ)2, a strong proteasome inhibitor effective at inducing cell paraptosis. In vivo, the Cu2+‐responsive HQ‐releasing micelles respond to elevated tumor Cu2+ levels or externally administered Cu2+ and effectively inhibit the growth of human breast adenocarcinoma doxorubicin‐resistant (MCF‐7/ADR) tumors. Compared with other nanomedicines that overcome drug resistance via delivering several agents or even siRNA, this paraptosis‐inducing nanomedicine provides a simple but potent approach to overcoming cancer drug resistance.

Transforming growth factor beta 1 (TGF-β1) is the most potent inhibitor of myogenic differentiation (MyoD) of rhabdomyosarcoma (RMS); however, the underlying mechanisms of this inhibition remain unclear. In this study, we identified novel TGF-β1-related microRNAs (miRNAs); among these, miR-450b-5p is significantly regulated by TGF-β1. We provide evidence that TGF-β1 exerts it function by suppressing miR-450b-5p. Both in cultured cells and tumor implants, miR-450b-5p significantly arrested the growth of RMS and promoted its MyoD. Utilizing a bioinformatics approach, we identified miR-450b-5p target mRNAs. Among these candidates, only the expression of ecto-NOX disulfide-thiol exchanger 2 (ENOX2) and paired box 9 (PAX9) was augmented by miR-450b-5p knockdown examined by western blot; the engineered inhibition antagonized TGF-β1-mediated differentiation inhibition. Furthermore, we found that the Smad3 and Smad4 pathways, but not Smad2, are the principal mediator of TGF-β1 suppression of miR-450b-5p. Taken together, these results suggest that disrupting the TGF-β1 suppression of miR-450b-5p, or knockdown of ENOX2 and PAX9, are effective approaches in inducing RMS MyoD.

Objectives Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TLLGNPPA) is a relatively rare nasopharyngeal tumor. We performed morphological characterization, immunohistochemical profiling, and investigated gene mutations. We also provide clinical follow-up data and brief review of the literature. Methods Immunohistochemistry was used to evaluate the expression of TTF-1, CK19, CK7, EMA, TG, Pax-8, CK5/6, S100, and Ki-67. Additionally, in situ hybridization was utilized to identify the presence of EBV. We investigated mutations in hot-spot exons of KRAS/NRAS/BRAF to rule out common mutations seen in thyroid tumors. Results Histopathologic examination of four cases identified tumors that were mainly occupied by papillary architectures. One case had a predominantly glandular structure. The tumors expressed TTF-1 and CK19, while TG and Pax-8 were negative. S100 was moderately expressed focally in three cases. Conclusions While TLLGNPPA displays a morphological resemblance to papillary thyroid carcinoma (PTC), it is vital to differentiate nasopharyngeal metastasis from PTC for appropriate treatment.

BackgroundLung cancer in nonsmokers tends to be driven by a single somatic mutation or a gene fusion. KIF5B-RET fusion is an oncogene identified in non-small cell lung cancers. In this study, we verified the oncogenic activity of KIF5B-RET fusion and investigated how KIF5B-RET activates the specific signaling pathways for cellular transformation. We aimed to provide a basis for the further development of the therapy for KIF5B-RET positive lung cancer patients.MethodsRT-PCR was used to screen for KIF5B-RET fusions in Chinese lung cancer patients. To verify the oncogenic activity of KIF5B-RET kinase in lung cancer cells, we manipulated its expression genetically followed by colony formation and tumor formation assays. The mechanism by which KIF5B-RET kinase induces proliferation was investigated by western blot, coimmunoprecipitation, and administration of RET, MAPK and STAT3 inhibitors.ResultsOur study identified a KIF5B-RET fusion in Chinese NSCLC patients and demonstrated that KIF5B-RET transfected cells showed a significantly increased proliferation rate and colony-forming ability. Furthermore, we found that KIF5B-RET fusion kinase induced multilevel activation of STAT3 at both Tyr705 and Ser727, and KIF5B-RET-STAT3 signaling related inhibitors repressed the proliferation and tumorigenicity of lung cancer cells significantly.ConclusionsOur data suggest that KIF5B-RET promotes the cell growth and tumorigenicity of non-small cell lung cancers through multilevel activation of STAT3 signaling, providing possible strategies for the treatment of KIF5B-RET positive lung cancers.

Metastasis is responsible for more than 90% of the mortality observed among patients with breast cancer. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is a novel member of the PEBP family and functions as an anti-apoptotic molecule. Here, we found that the metastatic MDA-MB-231 breast cancer cells expressed much higher levels of hPEBP4 than the nonmetastatic MCF-7 breast cancer cells and that the expression levels of hPEBP4 were positively correlated with the metastasis of clinical breast cancer. The hPEBP4 overexpression in the MDA-MB-231 cells significantly promoted cell invasion in vitro and increased the development of lymph node metastasis in vivo. Conversely, the silencing of hPEBP4 suppressed the cell-invasive ability both in vitro and in vivo. Further investigation showed that hPEBP4 promoted the expression or activity of the metastasis-related proteinases MMP (matrix metalloproteinase) 2, MMP9 and MMP13. This hPEBP4-potentiated cell invasion and MMP expression is due to an increase in Akt activation. Knockdown of Akt restored hPEBP4-induced breast tumor metastasis in the hPEBP4-MDA-MB-231 xenograft mouse model. Moreover, we found that hPEBP4 functioned as a scaffolding molecule and enhanced the association of Akt with Src to promote Akt tyrosine phosphorylation, a prerequisite for the full activation of Akt, in a phosphatidylethanolamine-binding domain-dependent manner. Given the present information about human breast cancer, these functional data from cell culture and animal studies suggest that, in human breast cancer hPEBP4 is a novel and clinically relevant metastasis accelerator gene and may be a new diagnostic marker and therapeutic target for breast cancer metastasis.

Protein arginine methyltransferase 1 (PRMT1) is the predominant asymmetric (type I) methyltransferase in mammalian cells. Mounting evidence suggested that PRMT1 is essential to embryonic development and tumor pathogenesis, but its role in normal adult hematopoiesis is less studied. We used a Prmt1 conditional knockout (KO) mouse model to identify the role of PRMT1 in normal adult hematopoiesis. The results indicated that deletion of PRMT1 results in anemia and leukopenia, reducing terminal erythroid and lymphocyte differentiation. Additionally, we found a significant decrease of megakaryocyte progenitors (MkPs) compared with similarly treated littermate control mice. The frequency of short-term hematopoietic stem cells (ST-HSCs) and granulocyte-macrophage progenitors (GMPs) populations were significantly lower in PRMT1 f/f /Mx1-CRE bone marrow (BM) compared with littermate control mice. Importantly, in-vitro replating assays and BM transplantation results revealed that PRMT1 KO results in reduced hematopoietic stem and progenitor cells (HSPCs) self-renewal capacity. Thus, we conclude that PRMT1 is required for hematopoietic differentiation and the competitive fitness of HSPCs, and we believed that PRMT1 serves as a key epigenetic regulator of normal hematopoiesis that occurs throughout life.

Fine-needle aspiration cytology (FNAC) is widely used for diagnosing thyroid nodules. However, there has been no specific investigation about the puncture feeling of grittiness. The aim of the present study was to see if the puncture feeling of grittiness during fine-needle aspiration procedure, combined with standard FNAC, could improve the accuracy in diagnosing thyroid cancer. A total of one thousand five hundred and thirty-one thyroid FNAC specimens acquired between January 2013 and January 2017 were retrospectively retrieved. All cases underwent surgical intervention. The FNAC diagnoses and puncture feeling of grittiness were evaluated and compared with the results of final histopathological diagnoses. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of diagnosis for thyroid nodules by FNAC alone, puncture feeling of grittiness alone, and the combination of FNAC plus grittiness were calculated respectively. The findings of our study suggest that puncture feeling of grittiness is a useful adjunct. Adding puncture feeling of grittiness to FNAC can significantly enhance the ability to differentiate malignant thyroid nodules from benign thyroid nodules. More importantly, we found that puncture feeling of grittiness is surprising trust-worthy in being near perfectly reproducible per individual radiologist, and among different operators.