Tumor-associated macrophages (TAMs) are the most abundant inflammatory infiltrates in the tumor microenvironment and contribute to lymph node (LN) metastasis. However, the precise mechanisms of TAMs-induced LN metastasis remain largely unknown. Herein, we identify a long noncoding RNA, termed Lymph Node Metastasis Associated Transcript 1 (LNMAT1), which is upregulated in LN-positive bladder cancer and associated with LN metastasis and prognosis. Through gain and loss of function approaches, we find that LNMAT1 promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis. Mechanistically, LNMAT1 epigenetically activates CCL2 expression by recruiting hnRNPL to CCL2 promoter, which leads to increased H3K4 tri-methylation that ensures hnRNPL binding and enhances transcription. Furthermore, LNMAT1-induced upregulation of CCL2 recruits macrophages into the tumor, which promotes lymphatic metastasis via VEGF-C excretion. These findings provide a plausible mechanism for LNMAT1-modulated tumor microenvironment in lymphatic metastasis and suggest that LNMAT1 may represent a potential therapeutic target for clinical intervention in LN-metastatic bladder cancer.

Several studies have suggested the involvement of cutaneous human papillomaviruses (HPVs) in the development of nonmelanoma skin cancers. Here we have characterized the in vitro properties of E7 proteins of three cutaneous HPV types, 10, 20, and 38, which are frequently detected in skin specimens. We show that HPV38 E7 is able to inactivate the tumor suppressor pRb and induces loss of G 1 /S transition control, a key event in carcinogenesis. In contrast, HPV10 and HPV20 E7 proteins do not display these in vitro transforming activities. We also show that the two early proteins E6 and E7 of HPV38 are sufficient to corrupt the cell cycle and senescence programs in primary cells, inducing active and long-lasting proliferation of primary human keratinocytes, the natural host cells. Our study shows that E6 and E7 of this cutaneous HPV type have transforming activity in primary human cells, suggesting a role for HPV38 infection in skin carcinogenesis. In further support of such a role, we detected HPV38 DNA in approximately 50% of nonmelanoma skin cancers, but only in 10% of healthy skin specimens (P < 0.001).Nonmelanoma skin cancer is the most frequently occurring malignancy in the Caucasian population (34,38,47). Although these cancers have a good prognosis and are not normally associated with mortality, an increasing incidence of other invasive cancers and cancer mortality following nonmelanoma skin cancers has been reported (17,24,28,29). Several lines of evidence suggest the involvement of an infective agent in the etiology of this condition. Patients suffering from a rare genetic immune suppression termed epidermodysplasia verruciformis and individuals under long-lasting immunosuppression are prone to develop these cancers (21,22,30,37). Epidermodysplasia verruciformis patients are highly susceptible to human papillomavirus (HPV) infections by a specific subgroup of cutaneous HPVs, the so-called epidermodysplasia verruciformis types (e.g., HPV5 and HPV8), that lead to extensive verrucosis of confluent flat warts (22,30,37). In approximately 30% of cases, the HPV lesions develop into multifocal squamous cell carcinomas.Supporting the infectious role of cutaneous HPV types in the tumorigenesis of nonmelanoma skin cancers is the fact that other members of the papillomavirus family are clearly oncogenic (55). Indeed, clinical, epidemiological, and molecular data have demonstrated that mucosal high-risk HPV types (e.g., high-risk HPV16 and HPV18) are the etiological agents of anogenital cancers as well as a subgroup of head and neck cancers (55). The early region of these HPV types encodes two oncoproteins, E6 and E7, which associate with and neutralize the cellular tumor suppressors p53 and retinoblastoma (pRb), respectively (32,36).Independent studies suggest that cutaneous HPV types may also be involved in the development of squamous cell carcinoma and basal cell carcinomas in the general population (6,7,14,43). These indications are based only on studies assessing viral DNA presence in skin tumors by PCR, which ha...

Castration-resistant prostate cancer (CRPC) that occurs after the failure of androgen deprivation therapy is the leading cause of deaths in prostate cancer patients. Thus, there is an obvious and urgent need to fully understand the mechanism of CRPC and discover novel therapeutic targets. Long noncoding RNAs (lncRNAs) are crucial regulators in many human cancers, yet their potential roles and molecular mechanisms in CRPC are poorly understood. In this study, we discovered that an lncRNA HOXD-AS1 is highly expressed in CRPC cells and correlated closely with Gleason score, T stage, lymph nodes metastasis, and progression-free survival. Knockdown of HOXD-AS1 inhibited the proliferation and chemo-resistance of CRPC cells in vitro and in vivo. Furthermore, we identified several cell cycle, chemo-resistance, and castration-resistance-related genes, including PLK1, AURKA, CDC25C, FOXM1, and UBE2C, that were activated transcriptionally by HOXD-AS1. Further investigation revealed that HOXD-AS1 recruited WDR5 to directly regulate the expression of target genes by mediating histone H3 lysine 4 tri-methylation (H3K4me3). In conclusion, our findings indicate that HOXD-AS1 promotes proliferation, castration resistance, and chemo-resistance in prostate cancer by recruiting WDR5. This sheds a new insight into the regulation of CRPC by lncRNA and provides a potential approach for the treatment of CRPC.

The E6 and E7 of the cutaneous human papillomavirus (HPV) type 38 immortalize primary human keratinocytes, an event normally associated with the inactivation of pathways controlled by the tumour suppressor p53. Here, we show for the first time that HPV38 alters p53 functions. Expression of HPV38 E6 and E7 in human keratinocytes or in the skin of transgenic mice induces stabilization of wild-type p53. This selectively activates the transcription of DNp73, an isoform of the p53-related protein p73, which in turn inhibits the capacity of p53 to induce the transcription of genes involved in growth suppression and apoptosis. DNp73 downregulation by an antisense oligonucleotide leads to transcriptional re-activation of p53-regulated genes and apoptosis. Our findings illustrate a novel mechanism of the alteration of p53 function that is mediated by a cutaneous HPV type and support the role of HPV38 and DNp73 in human carcinogenesis.