A transcribed ultraconserved noncoding RNA, uc.285+, promotes colorectal cancer proliferation through dual targeting of CDC42 by directly binding mRNA and protein.

The transcribed ultraconserved region (T-UCR) belongs to a new type of lncRNAs that are conserved in homologous regions of the rat, mouse and human genomes. A lot of research has reported that differential expression of T-UCRs can influence the development of various cancers, revealing the ability of T-UCRs as new therapeutic targets or potential cancer biomarkers. Most studies on the molecular mechanisms of T-UCRs in cancer have focused on ceRNA regulatory networks and interactions with target proteins, but the present study reveals an innovative dual-targeted regulatory approach in which T-UCRs bind directly to mRNAs and directly to proteins. We screened T-UCRs that may be related to colorectal cancer (CRC) by performing a whole-genome T-UCR gene microarray and further studied the functional mechanism of T-UCR uc.285+ in the development of CRC. Modulation of uc.285+ affected the proliferation of CRC cell lines and influenced the expression of the CDC42 gene. We also found that uc.285+ promoted the proliferation of CRC cells by directly binding to CDC42 mRNA and enhancing its stability while directly binding to CDC42 protein and affecting its stability. In short, our research on the characteristics of cell proliferation found that uc.285+ has a biological function in promoting CRC proliferation. uc.285+ may have considerable potential as a new diagnostic biomarker for CRC.

SNHG18 inhibits bladder cancer cell proliferation by increasing p21 transcription through destabilizing c-Myc protein.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been confirmed to play important roles in various cancers including bladder cancer (BC). The precise expression pattern of lncRNA small nucleolar RNA host gene 18 (SNHG18) in BC and its mechanisms of action have not been fully explored. MATERIALS AND METHODS: The expression of SNHG18 was evaluated by RT-qPCR in bladder cancer clinical samples and human bladder cancer cell lines, and stable cell lines overexpressing SNHG18 were constructed. The effect of SNHG18 on the proliferation of bladder cancer cells was detected by soft agar colony formation test, ATP activity test and subcutaneous tumorigenesis model in nude mice. The specific mechanism of SNHG18 inhibition of bladder cancer proliferation was studied by flow cytometry, western blotting, dual luciferase reporter gene assay and protein degradation assay. RESULTS: We found that SNHG18 is significantly downregulated in BC tissues and cell lines. Kaplan-Meier analysis showed that SNHG18 expression is positively correlated with survival in BC patients. Ectopic overexpression of SNHG18 significantly inhibited the proliferation of BC cells in vitro and in vivo. Further mechanistic investigations demonstrated that SNHG18 inhibited c-Myc expression by modulating the ubiquitination-proteasome pathway and that c-Myc is the critical transcription factor that mediates SNHG18 inhibition of BC growth by directly binding to the p21 promoter, which was attributed with significant p21 accumulation. CONCLUSIONS: SNHG18 promotes the transcription and expression of p21 by inhibiting c-Myc expression, leading to G0-G1 arrest and inhibiting the proliferation of bladder cancer cells. These findings highlight a novel cell cycle regulatory mechanism involving the SNHG18/c-Myc/p21 pathway in BC pathogenesis and could potentially lead to new lncRNA-based diagnostics and/or therapeutics for BC.

The pivotal regulatory factor circBRWD1 inhibits arsenic exposure-induced lung cancer occurrence by binding mRNA and regulating its stability.

Multiple studies have indicated that circular RNAs (circRNAs) play a regulatory role in different stages of tumors by interacting with various molecules. With continuous in-depth research on the biological functions of circRNAs, increasing evidence has shown that circRNAs play important roles in carcinogenesis caused by environmental pollutants. However, the function and mechanism of circRNAs in arsenic exposure-induced lung cancer occurrence have not been reported. In this study, RNA sequencing and qPCR assays revealed that the expression of circBRWD1 was decreased in BEAS-2B-As cells and multiple lung cancer cell lines. Silencing circBRWD1 promoted cell viability and proliferation, inhibited cell apoptosis, and accelerated the G0/G1 phase transition in BEAS-2B-As cells; however, these functions were abrogated by circBRWD1 overexpression. Mechanistically, under arsenic exposure, expression of decreased circBRWD1 led to enhanced stability of the mRNA to which it directly binds (c-JUN, c-MYC, and CDK6 mRNA), increasing its expression. This mechanism promotes the malignant transformation of lung cells and ultimately leads to lung cancer. Our findings thus reveal the molecular mechanism of arsenic carcinogenesis.

Circular RNA circLAMA3 inhibits the proliferation of bladder cancer by directly binding an mRNA.

The circular RNA (circRNA) circLAMA3 is significantly downregulated in bladder cancer tissues and cell lines. However, its function in bladder cancer has not yet been explored, and further research is needed. In this study, functional experiments demonstrated that circLAMA3 significantly inhibited the proliferation, migration, and invasion of bladder cancer cells and inhibited bladder cancer growth in vivo. Mechanistically, circLAMA3 directly binds to and promotes the degradation of MYCN mRNA, thereby reducing the MYCN protein expression in bladder cancer cells. Decreased expression of the MYCN protein inhibits the promoter activity and expression of CDK6. Ultimately, circLAMA3 affects DNA replication by downregulating CDK6, resulting in G0/G1 phase arrest and inhibition of bladder cancer proliferation. In summary, we report a potential novel regulatory mechanism via which a circRNA directly binds an mRNA and thereby regulates its fate. Moreover, circLAMA3 significantly affects the progression of bladder cancer and has potential as a diagnostic biomarker and therapeutic target for bladder cancer.

Circular RNA circGLIS3 promotes bladder cancer proliferation via the miR-1273f/SKP1/Cyclin D1 axis.

Extensive research confirmed that circRNA can play a regulatory role in various stages of tumors by interacting with various molecules. Identifying the differentially expressed circRNA in bladder cancer and exploring its regulatory mechanism on bladder cancer progression are urgent. In this study, we screened out a circRNA-circGLIS3 with a significant upregulation trend in both bladder cancer tissues and cells. Bioinformatics prediction results showed that circGLIS3 may be involved in multiple tumor-related pathways. Function gain and loss experiments verified circGLIS3 can affect the proliferation, migration, and invasion of bladder cancer cells in vitro. Moreover, silencing circGLIS3 inhibited bladder cancer cell growth in vivo. Subsequent research results indicated circGLIS3 regulated the expression of cyclin D1, a cell cycle-related protein, and cell cycle progression. Mechanically, circGLIS3 upregulates the expression of SKP1 by adsorbing miR-1273f and then promotes cyclin D1 expression, ultimately promoting the proliferation of bladder cancer cells. In summary, our study indicates that circGLIS3 plays an oncogene role in the development of bladder cancer and has potential to be a candidate for bladder cancer.

Super-Enhancer LncRNA LINC00162 Promotes Progression of Bladder Cancer.

Due to the lack of effective early diagnostic measures and treatment methods, bladder cancer has become a malignant tumor that seriously threatens people's lives and health. Here, we reported that LINC00162, a super-enhancer long noncoding RNA, was highly expressed in bladder cancer cells and tissues. And LINC00162 was negatively correlated with neighboring PTTG1IP expression. Knocking down LINC00162 expression can inhibit the proliferative activity of bladder cancer cells and the growth of transplanted tumors in vivo, while knocking down the expression of PTTG1IP could restore the proliferative activity of bladder cancer cells. In addition, both LINC00162 and PTTG1IP were found to be able to bind to THRAP3, a transcription-related protein. And THRAP3 can regulate PTTG1IP expression. Finally, we demonstrated a mechanism that LINC00162 could regulate PTTG1IP expression through binding THRAP3. This study provided a potential target molecule for clinical treatment of bladder cancer.

MiRNA-516a promotes bladder cancer metastasis by inhibiting MMP9 protein degradation via the AKT/FOXO3A/SMURF1 axis.

BACKGROUND: Metastasis is the leading cause of death in patients with bladder cancer (BC). However, current available treatments exert little effects on metastatic BC. Moreover, traditional grading and staging have only a limited ability to identify metastatic BC. Accumulating evidence indicates that the aberrant expression of microRNA is intimately associated with tumor progression. So far, many miRNAs have been identified as molecular targets for cancer diagnosis and therapy. This study focused on the role of miR-516a-5p (miR-516a) in BC. METHODS: MiR-516a expression and its downstream signaling pathway were detected using molecular cell biology and biochemistry approaches and techniques. Fresh clinical BC tissue was used to study the clinicopathological characteristics of patients with different miR-516a expression. The biological functions of miR-516a in BC were tested both in vivo and in vitro. RESULTS: A more invasive BC phenotype was significantly and positively correlated with miR-516a overexpression in BC patients. MiR-516a inhibition significantly decreased BC cell invasion and migration in vitro and in vivo. Furthermore, miR-516a attenuated the expression of PH domain leucine-rich repeat-containing protein phosphatase 2 protein and inhibited SMAD-specific E3 ubiquitin protein ligase 1 transcription by activating the AKT/Forkhead box O3 signaling pathway, which stabilized MMP9 and slowed down its proteasomal degradation, ultimately promoting BC motility and invasiveness. CONCLUSIONS: Our findings reveal the crucial function of miR-516a in promoting BC metastasis, and elucidate the molecular mechanism involved, suggesting that miR-516a may be a promising novel diagnostic and therapeutic target for BC.