Loss of miR-449a-caused PrLZ overexpression promotes prostate cancer metastasis

Abstract

Distant metastasis is the worst prognostic factor for PCa patients. It has been reported that miR-449a enhances radiosensitivity of prostate cancer cells, but the function of miR449a in metastasis of prostate cancer is mainly unknown. In the present study, we strove to investigate the function and diagnostic value of miR-449a in metastasis of prostate cancer. qRT-PCR was used to quantify the expression of miR449a and PrLZ in PCa cell lines and tissues. We found that miR449a expression was decreased in PCa cell lines. Moreover, miR-449a was downregulated in PCa tissues, especially in primary lesion tissues of metastatic PCa patients. CCK8, FACS, Transwell and tube formation assay were performed to assess growth and metastasis of PCa cells in vitro. Lentivirus mediated miR-449a overexpression suppressed proliferation of LNcap and PC-3, and miR-449a also significantly inhibited invasion and angiogenesis ability of LNcap and PC-3. IHC showed that PrLZ was upregulated in PCa tissues. Luciferase assay and western blotting verified that miR-449a targeted PrLZ expression. Moreover, PrLZ shRNA also significantly suppressed proliferation and metastasis of LNcap and PC-3. In addition, western blotting revealed that miR-449a overexpression and PrLZ shRNA all remarkably inhibited the stemness features in LNcap and PC-3. Furthermore, BALB/c nude mouse subcutaneous xenograft model was uesd to verify the function of miR-449a and PrLZ. Our results showed that miR-449a and PrLZ shRNA significantly suppressed PC-3 tumorigenesis and metastasis in vivo. Our studies suggested that miR-449a decreased in malignant process of PCa and was accompanied by excess expression of PrLZ. The loss of miR-449a caused PrLZ overexpression regulated prostate cancer progression and metastasis via regulating the stemness features of prostate cancer cells. The diagnostic value of miR-449a as a distant metastasis predictor of PCa needs further investigation.

microRNA: The Impact on Cancer Stemness and Therapeutic Resistance

“…The main mechanism and function of PrLZ, a newly-discovered PCa-specific oncoprotein, in PCa development deserves further investigations, and the miR-499a/PrLZ axis could be a potential target for eradicating PCa CSCs [103].…”

The Functional Role of Prostate Cancer Metastasis-related Micro-RNAs

“…MMP2 was identified as a direct target of miR-130b(92) and acts as a promoter of metastasis through degradation of the extracellular matrix (93) (Figure 5).miR-449a targets prostate leucine zipper gene (PrLZ). Downregulation of miR-449 is related to PC clinical stage and distant metastasis(94). miR-449a suppressed proliferation, promoted apoptosis and restricted invasion and tube formation by LNCaP and PC3 cells(94).…”

Long noncoding RNA SNHG7 contributes to cell proliferation, migration, invasion and epithelial to mesenchymal transition in non‐small cell lung cancer by regulating miR‐449a/TGIF2 axis

“…For instance, miR‐449a expression was reduced in breast cancer as well as NSCLC and miR‐449a retarded cell viability, migration and invasion in those cancer types by regulating the PLAGL2 and NF‐kB pathway, respectively . Interestingly, a reduced expression of miR‐449a contributed to growth and metastasis of prostate cancer cells by targeting PrLZ . Moreover, antitumor compounds ailanthone and neferine were capable of cascading the production of miR‐449a, thereby suppressing cell growth in acute myeloid leukemia and gastrointestinal stromal cancer .…”