Cervical cancer (CC) is the third most common carcinoma and the fourth leading cause of cancer-associated mortality in women. Here, we report that MDM2-DHX9 interaction mediates CC motility and angiogenesis in a long noncoding RNAdependent fashion. A long noncoding RNA, named lnc-CCDST, is significantly downregulated in CC tissues, and binds to pro-oncogenic DHX9. DHX9 is upregulated in CC tissue, and promotes CC cell motility and angiogenesis. The lnc-CCDST and DHX9 interaction promotes DHX9 degradation through the ubiquitin proteasome pathway. Furthermore, DHX9 bound to E3 ubiquitin ligase MDM2, and this interaction is enhanced by lnc-CCDST. Thus, lnc-CCDST promotes DHX9 degradation by serving as a scaffold to facilitate the formation of MDM2 and DHX9 complexes. Moreover, HPV oncogenes E6 and E7 abolish the expression of lnc-CCDST resulting in the increase of DHX9. Our results have revealed a novel mechanism by which high-risk HPVs promote motility and angiogenesis of CC by inhibiting expression of lnc-CCDST to disrupt MDM2 and DHX9 interaction, and DHX9 degradation, and identified a potential therapeutic target for CC.
We suggest that activation of GPER exerts an inhibitory effect on colonic motility by promoting NO release from myenteric nitrergic nerves. These results raise a possibility that GPER may be involved in mediating the inhibitory effect of estrogen on colonic motor functions, via a non-genomic, neurogenic mechanism.
While the application of early screening and HPV vaccines has reduced the incidence and mortality rates of cervical cancer, it remains the third most common carcinoma and fourth leading cause of cancer-associated death among women worldwide. The precise mechanisms underlying progression of cervical cancer are not fully understood at present. Here, we detected significant down-regulation of 15-hydroxyprostaglandin dehydrogenase (HPGD) in cervical cancer tissues. Overexpression of HPGD inhibited cervical cancer cell proliferation, migration and anchorage-independent growth to a significant extent. To clarify the mechanisms underlying HPGD down-regulation in cervical cancer, miRNA microarray, bioinformatics and luciferase reporter analyses were performed. HPGD was identified as a direct target of miR-146b-3p displaying up-regulation in cervical cancer tissues. Similar to the effects of HPGD overexpression, down-regulation of miR-146b-3p strongly suppressed proliferation, migration and anchorage-independent growth of cervical cancer cells. Furthermore, HPGD negatively regulated activities of STAT3 and AKT that promote cervical cancer cell proliferation. Notably, HPV oncogenes E6 and E7 were determined as potential contributory factors to these alterations. Our results collectively suggest that the HPGD/miR-146b-3p axis plays a significant role in cervical cancer and may serve as a potentially effective therapeutic target.
Depression remains one of the most prevalent psychiatric disorders, and it has been confirmed that it is related to dysfunction of the microbiota-gut-brain axis. Manipulation of gut microenvironment by probiotics...
Kaposi's sarcoma (KS), a highly invasive and angiogenic tumor of endothelial spindle-shaped cells, is the most common AIDS-associated cancer caused by KS-associated herpesvirus (KSHV) infection. KSHV-encoded viral FLICE-inhibitory protein (vFLIP) is a viral oncogenic protein, but its role in the dissemination and angiogenesis of KSHV-induced cancers remains unknown. Here, we report that vFLIP facilitates cell migration, invasion, and angiogenesis by downregulating the SAP18-HDAC1 complex. vFLIP degrades SAP18 through a ubiquitin-proteasome pathway by recruiting E3 ubiquitin ligase TRIM56. Further, vFLIP represses HDAC1, a protein partner of SAP18, by inhibiting Nanog occupancy on the HDAC1 promoter. Notably, vFLIP impairs the interaction between the SAP18/HDAC1 complex and p65 subunit, leading to enhancement of p65 acetylation and NF-κB activation. Our data suggest a novel mechanism of vFLIP activation of the NF-κB by decreasing the SAP18/HDAC1 complex to promote the acetylation of p65 subunit, which contributes to vFLIPinduced activation of the NF-κB pathway, cell invasion, and angiogenesis. These findings advance our understanding of the mechanism of KSHV-induced pathogenesis, and providing a rationale for therapeutic targeting of the vFLIP/SAP18/HDAC1 complex as a novel strategy of AIDS-KS.
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