Tumor Suppressor In Cancer Progression Research Articles

TRAF7-targeted HOXA5 acts as a tumor suppressor in prostate cancer progression and stemness via transcriptionally activating SPRY2 and regulating MEK/ERK signaling

Homeobox A5 (HOXA5), a homeodomain transcription factor, is considered a tumor suppressor in cancer progression; however, its function in prostate cancer (PCa) remains unclear. This study focused on the relevance of HOXA5 in PCa progression. We identified the downregulation of HOXA5 in PCa tissues based on the TCGA database and further verified in 30-paired PCa and adjacent normal tissues. Functional studies revealed that HOXA5 upregulation impaired the stem-like characteristics and malignant behaviors of PCa cells in vitro and in vivo. Mechanistically, HOXA5 was found to be regulated by tumor necrosis factor receptor-associated factor 7 (TRAF7), a putative E3-ubiquitin ligase. We observed that TRAF7 was overexpressed in PCa and subsequently enhanced the degradation of HOXA5 protein via its ubiquitin ligase activity, contributing to the acquisition of an aggressive PCa phenotype. For its downstream mechanism, we demonstrated that sprouty RTK signaling antagonist 2 (SPRY2) served as a downstream target of HOXA5. HOXA5 could directly bind to the SPRY2 promoter, thereby regulating the SPRY2-mediated MEK/ERK signaling pathway. Silencing SPRY2 largely compromised the tumor-suppressive effect of HOXA5 in PCa progression and cancer stemness. Our findings highlight the previously-underappreciated signaling axis of TRAF7–HOXA5–SPRY2, which provides a novel prognostic and therapeutic target for PCa treatment.

MiR-138-5p Inhibits the Proliferation of Gastric Cancer Cells by Targeting DEK.

BackgroundIncreasing evidence suggests that microRNAs (miRNAs) play critical roles in cancer progression. Therefore, investigating the function of miRNAs that are aberrantly expressed in gastric cancer (GC) and characterizing the involved underlying mechanism are essential for the treatment of gastric cancer. MiR-138-5p was found to be down-regulated in multiple cancers, which acted as a tumor suppressor in cancer progression; however, whether and how miR-138-5p regulates the malignant behaviors of GC has not been fully understood.MethodsThe level of miR-138-5p in GC tissues and cell lines was detected by RT-qPCR. The effects of miR-138-5p on the growth of GC cells were evaluated by the in vitro Cell Counting Kit-8 (CCK-8) assay, cell apoptosis, cell cycle analysis, wound-healing assay, and in vivo xenograft mice model. The targets of miR-138-5p were predicted using the miRDB online tool, confirmed by luciferase report assay and Western blot.ResultsMiR-138-5p was frequently decreased in GC tissues and cell lines. Decreased expression of miR-138-5p was significantly associated with the lymph node metastasis of GC patients. Overexpression of miR-138-5p suppressed GC cell proliferation, migration, increased cell apoptosis as well as inhibited the tumor growth in vivo. DEK oncogene was predicted as a potential target of miR-138-5p. MiR-138-5p bound the 3ʹ-UTR of DEK and inhibited the level of DEK in GC cells. Restoration of DEK abrogated miR-138-5p overexpression-mediated suppression of GC cell proliferation and cell cycle arrest.ConclusionOur results demonstrated the anti-cancer role of miR-138-5p in GC by targeting DEK, which suggested miR-138-5p as a potential therapeutic target for the treatment of patient with GC.

Antagonism between HTRA3 and TGFβ1 Contributes to Metastasis in Non-Small Cell Lung Cancer.

High temperature requirement A3 (HTRA3, long and short isoforms) is a member of the HtrA family and has been implicated as a tumor suppressor in cancer progression in multiple cancer types, yet its molecular functions in non-small cell lung cancer (NSCLC) are not well understood. Here, we report that decreased levels of HTRA3 negatively correlate with elevated TGFβ1 in lung tumor tissue with metastasis. Furthermore, high expression of HTRA3 indicated better prognosis independent of TGFβ1 expression. In NSCLC cell lines, exogenous TGFβ1 significantly downregulated the level of HTRA3, especially the long isoform, during induction of epithelial-mesenchymal transition (EMT). Mechanistically, c-Jun, which is elevated by TGFβ1, directly bound the promoter of HTRA3-L and inhibited its transcription. As a negative feedback loop, overexpression of HTRA3-L attenuated TGFβ1-mediated invasion-metastasis cascades via activation of SMAD2/3 and sensitized cells to anti-PD-L1 treatment. Taken together, our findings suggest that in the early stages of cancer, overexpressed HTRA3 acts as a brake on the oncogenic effects of TGFβ1 and inhibits tumor metastasis. In later stages, the role of HTRA3 is weakened and TGFβ1 efficiently promotes EMT in the absence of the HTRA3 brake. SIGNIFICANCE: This study provides new mechanistic insight of the interaction between HTRA3 and TGFβ in lung cancer by illustrating that HTRA3 is a novel mediator acting as a suppressor of TGFβ1-related oncogenic effects.