NF-κB is a critical link between inflammation and cancer, but whether long non-coding RNAs (lncRNAs) regulate its activation remains unknown. Here, we identify an NF-KappaB Interacting LncRNA (NKILA), which is upregulated by NF-κB, binds to NF-κB/IκB, and directly masks phosphorylation motifs of IκB, thereby inhibiting IKK-induced IκB phosphorylation and NF-κB activation. Unlike DNA that is dissociated from NF-κB by IκB, NKILA interacts with NF-κB/IκB to form a stable complex. Importantly, NKILA is essential to prevent over-activation of NF-κB pathway in inflammation-stimulated breast epithelial cells. Furthermore, low NKILA expression is associated with breast cancer metastasis and poor patient prognosis. Therefore, lncRNAs can directly interact with functional domains of signaling proteins, serving as a class of NF-κB modulators to suppress cancer metastasis.

SUMMARY Tumor-associated macrophages (TAMs) can influence cancer progression and metastasis, but the mechanism remains unclear. Here, we show that breast TAMs abundantly produce CCL18, and its expression in blood or cancer stroma is associated with metastasis and reduced patient survival. CCL18 released by breast TAMs promotes the invasiveness of cancer cells by triggering integrin clustering and enhancing their adherence to extracellular matrix. Furthermore, we identify PITPNM3 as a functional receptor for CCL18 that mediates CCL18 effect and activates intracellular calcium signaling. CCL18 promotes the invasion and metastasis of breast cancer xenografts, whereas suppressing PITPNM3 abrogates these effects. These findings indicate that CCL18 derived from TAMs plays a critical role in promoting breast cancer metastasis via its receptor, PITPNM3.

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Trastuzumab resistance emerges to be a major issue in anti-human epidermal growth factor receptor 2 (HER2) therapy for breast cancers. Here, we demonstrated that miR-21 expression was upregulated and its function was elevated in HER2 ؉ BT474, SKBR3, demonstrates therapeutic potential by sensitizing the malignancy to anti-HER2 treatment.Overexpression of human epidermal growth factor receptor 2 (HER2/NEU/c-ERBB2), 4 a member of the epidermal growth factor receptor (EGFR) family of 185 kDa, is found in 20 -35% of human breast cancers (1). Amplification of HER2 is linked to aggressive tumor behavior and poor clinical outcome with shorter disease-free intervals and overall survival in patients with early and advanced breast cancers (2). Tremendous efforts have been made to develop HER2-targeting cancer therapies, and a most successful strategy is the recombinant humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin) that specifically binds to the extracellular domain of HER2 and blocks its function. Clinical application of trastuzumab in adjuvant and metastatic settings has been shown to prolong the survival of patients with HER2 ϩ breast cancers (3). However, the response rate to trastuzumab monotherapy is less than 35%, whereas ϳ60% of patients with HER2 ϩ cancers on regimens combining trastuzumab with microtubule stabilizing drugs do not respond to treatment (4). Moreover, most patients who achieve an initial response develop resistance to trastuzumab within 1 year (5). Therefore, identifying the mechanisms responsible for trastuzumab resistance is important for the development of new therapeutic strategies.A number of mechanisms have been suggested for trastuzumab resistance, including dysregulation of downstream signaling pathways and compensated signaling by other EGF family members or through alternative pathways (6). Among them, reduced PTEN expression is a strong indicator to predict trastuzumab resistance in breast cancer patients. Further mechanistic study showed that loss of PTEN function in HER2 ϩ cancer cells leads to trastuzumab resistance by enhancing downstream PI3K/AKT phosphorylation and thus preventing trastuzumab-mediated growth arrest (7). However, how PTEN expression is silenced in trastuzumab resistance remains illusive.Micro-RNAs (miRNAs) are a class of small non-coding RNAs of ϳ22 nucleotides in size that are endogenously expressed in mammalian cells. They regulate gene expression by repressing mRNA translation or cleaving target mRNA. As a new family of gene regulators, miRNAs are involved in modulating multiple cellular pathways, including cell proliferation, differentiation, and apoptosis, and thus may function as oncogenes or tumor suppressing genes (8). Among them, oncogenic miRNAs, including miR-17-92 (9), miR-19a (10), miR-21 (11), miR-26a (12), miR-141 (13), miR-216a (14), miR-217 (14), miR-* This work was supported by National Natural Science Foundation of China Grants 30772550, 30801376, 30830110, 30831160515, 30921140312, 30973505, and 30945201, the Sun-Yat-Sen Excellen...

Abstract. MicroRNAs (miRNAs) are a type of small non-coding RNA molecule that performs an important role in post-transcriptional gene regulation. Since miRNAs were first identified in 1993, a number of studies have demonstrated that they act as tumor suppressors or oncogenes in human cancer, including colorectal, lung, brain, breast and liver cancer, and leukemia. Large high-throughput studies have previously revealed that miRNA profiling is critical for the diagnosis and prognosis of patients with cancer, while certain miRNAs possess the potential to be used as diagnostic and prognostic biomarkers or therapeutic targets in cancer. The present study reviews the studies and examines the roles of miRNAs in cancer diagnosis, prognosis and treatment, and discusses the potential therapeutic modality of exploiting miRNAs.