Early studies indicated that the androgen receptor (AR) might play important roles in the regulating of the initiation and progression of hepatocellular carcinoma (HCC), but its linkage to the ...surrounding macrophages and their impacts on the HCC progression remain unclear. Here we found that macrophages in liver cancer might function via altering the microRNA, miR-92a-2-5p, in exosomes to decrease liver cancer cells AR expression, which might then lead to increase the liver cancer cells invasion. Mechanism dissection revealed that miR-92a-2-5p from the exosomes could target the 3'UTR of AR mRNA to suppress AR translation, altering the PHLPP/p-AKT/β-catenin signaling to increase liver cancer cells invasion. Preclinical studies demonstrated that targeting this newly identified signaling with miR-92a-2-5p inhibitors led to suppress liver cancer progression. Together, these findings suggest that macrophages in the liver cancer tumor microenvironment may function via exosomes to regulate liver cancer progression, and targeting this newly identified macrophages/exosomes-miR-92a-2-5p/AR/PHLPP/p-AKT/β-catenin signaling may help in the development of novel treatment strategies to better suppress liver cancer progression.
Early studies indicated that estrogen receptor α (ERα) might impact the progression of hepatocellular carcinoma (HCC). However, the detailed mechanisms, especially its linkage to the gelsolin ...(GSN)-mediated cell invasion, remain unclear. Here we found that ERα could decrease HCC cell invasion via suppressing the circular RNA-SMG1.72 (circRNA-SMG1.72) expression via transcriptional regulation through directly binding to the 5' promoter region of its host gene SMG1, We showed that ERα-suppressed circ-SMG1.72 could sponge and inhibit the expression of the microRNA (miRNA, miR), miR-141-3p, which could then result in increasing the GSN messenger RNA translation via reduced miR binding to its 3' untranslated region (3'UTR). The preclinical study using an in vivo mouse model with orthotopic xenografts of HCC cells confirmed the in vitro data, and the human HCC clinical sample survey and tissue staining also confirmed the linkage of ERα/miR-141-3p/GSN signaling to the HCC progression. Together, our findings suggest that ERα can suppress HCC cell invasion via altering the ERα/circRNA-SMG1.72/miR-141-3p/GSN signaling, and targeting this newly identified signaling with small molecules may help in the development of novel therapies to better suppress the HCC progression.
RNF2 is a RING domain-containing E3 ubiquitin ligase that mediate histone H2A mono-ubiquitination to repress gene transcription, but its expression patterns and molecular function in hepatocellular ...carcinoma (HCC) remain unclear. Herein, we extracted data from TGCA database and validated RNF2 expression in our own cohort, which revealed that RNF2 was highly expressed in HCC and was associated with malignant characteristics and poor prognosis of HCC. Moreover, RNF2 was demonstrated to promote HCC metastasis via enhancing epithelial-mesenchymal transition (EMT) both in vitro and in vivo. Mechanistically, RNF2 repressed E-Cadherin transcription by increasing the deposition of H2K119ub at the E-Cadherin promoter region. In addition, RNF2-regulated crosstalk between H2AK119ub, H3K27me3 and H3K4me3 synergistically reduced E-Cadherin transcription, which promoted EMT and HCC metastasis. These results indicate that RNF2 played an oncogenic role in HCC progression via inducing EMT, and RNF2 could be a potential therapeutic target for HCC.
Liver cancer is one of the most lethal malignant tumors in the world. The high recurrence and mortality rate make it urgent for scientists and clinicians to find new targets for better treatment of ...liver cancer. Here, we found that circ-PRKAR1B expression was increased in the paired intrahepatic metastasis sample through high-throughput sequencing. Further experiments also confirmed its high expression both in carcinoma and metastasis when compared to the paired para-carcinoma and the paired carcinoma, respectively. Mechanism study showed that circ-PRKAR1B could promote liver cancer progression through the miR-432-5p/E2F3 pathway, and microRNA-432-5p could directly target the 3′ untranslated region (UTR) of E2F3 mRNA to suppress its translation, thereby influencing liver cancer cell invasion and migration capacities. Clinical data obtained by using online databases based on The Cancer Genome Atlas (TCGA) samples and the clinicopathological data of liver cancer patients who underwent surgery in our hospital in the past 2 years also confirmed the significance of circ-PRKAR1B/miR-432-5p/E2F3 signaling in liver cancer progression. Animal experiments also indicated that targeting this newly identified signaling by overexpressing microRNA-432-5p could suppress the progression of liver cancer. Together, our study suggests that circ-PRKAR1B plays an important role in the regulation of liver cancer progression, and targeting this new circ-PRKAR1B/miR-432-5p/E2F3 signaling may help us find new treatment strategies to better suppress liver cancer progression.
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High recurrence and mortality require clinicians to find new targets to better treat liver cancer. The study of Xiao et al. defined the role of circ-PRKAR1B in liver cancer progression through miR-432-5p/E2F3 signaling and builds a rationale to develop the signaling targeted therapies for better treatment of liver cancer.
The incidence and mortality of papillary thyroid cancer (PTC) have steadily increased. Although conventional therapies are very effective toward differentiated PTC patients, very limited therapeutic ...options are applicable to those patients with distant metastases. Therefore, better understanding of the molecular biology of metastatic PTC helps identify novel targets and facilitates the development of new therapies. In this study, we first found that testicular orphan receptor 4 (TR4) was significantly increased in PTC tumors spreading to lymph nodes compared to the paired primary tumors. Experimental evidence suggested that TR4 drove PTC progression via promoting its cell invasion and cell migration. Mechanistically, TR4 transcriptionally regulated the expression level of circ-filamin A (FLNA), which competed with matrix metalloproteinase 9 (MMP9) for microRNA (miR)-149-5p binding and led to an increased protein level of MMP9. Interruption assays with various gene manipulations verified that the TR4/circ-FLNA/miR-149-5p/MMP9 signaling axis played a central role in cell invasion and cell migration of PTC cells. Moreover, a xenografted mouse model also confirmed that the TR4/circ-FLNA signal promoted PTC tumor growth. Overall, our study pinpoints the oncogenic role of TR4 in PTC development, and the targeting of TR4/circ-FLNA/miR-149-5p/MMP9 signaling may be an alternative option for metastatic PTC patients.
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Very limited therapeutic options are applicable to papillary thyroid cancer (PTC) with distance metastasis. The study of Wang and co-workers defined the role of TR4 in PTC progression through circ-FLNA/miR-149-5p/MMP9 signaling and builds rationale to develop TR4-targeted therapies for better treatment of metastatic PTC.
Isocitrate dehydrogenase (IDH) mutations increase (R)-2-hydroxyglutarate (R-2HG) production; however, functional mechanisms of R-2HG in regulating cholangiocarcinoma (CCA) development remain to be ...further investigated. We first applied the CRISPR-Cas9 gene-editing system to create IDH1R132H-mutated CCA cells. Interestingly, our data showed that R-2HG could function through downregulating estrogen receptor alpha (ERα) and Yes-associated protein 1 (YAP1) pathways to decrease CCA growth. Detailed mechanistic studies revealed that R-2HG could target and degrade the fat mass and obesity-associated protein (FTO), the first identified mRNA demethylase. This reduced FTO can increase the N6-methyladenosine (m6A) to methylate the mRNA of ERα, and consequently decrease protein translation of the ERα. Further mechanistic studies revealed that ERα could transcriptionally suppress miR-16-5p expression, which could then increase YAP1 expression due to the reduced miR-16-5p binding to the 3′ UTR of YAP1. Furthermore, data from the pre-clinical animal model with implantation of IDH1R132H QBC939 cells demonstrated that R-2HG generated by the IDH1 mutation could downregulate ERα and YAP1 to suppress CCA tumor growth. Taken together, our new findings suggested that IDH1 mutation-induced R-2HG could suppress CCA growth via regulating the FTO/m6A-methylated ERα/miR16-5p/YAP1 signaling pathway. Upregulating R-2HG or downregulating the ERα signal by short hairpin RNA ERα (shERα) or antiestrogen could be effective strategies to inhibit CCA.
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Our study demonstrates that (R)-2-hydroxyglutarate (R-2HG), produced by IDH1/2 mutations, could suppress tumor growth in cholangiocarcinoma through regulating the FTO/m6A-methylated ERα/miR16-5p/YAP1 pathway.
Liver cancer is one of the most lethal malignant tumors in the world, and surgical resection is the main treatment for liver cancer. Liver failure due to insufficient residual liver volume is a fatal ...complication after hepatectomy. How to effectively increase the residual liver volume after hepatectomy and improve the safety of hepatectomy has always been a problem to be solved in liver surgery. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) effectively reduces the occurrence of liver failure due to insufficient residual liver volume after hepatectomy, thereby increasing the probability of radical resection by inducing rapid proliferation of residual liver tissue. However, the molecular mechanism of residual liver tissue regeneration after primary ALPPS (combined liver partition and portal vein ligation) remains unclear. Here, we found that lots of circular RNAs (circRNAs) are upregulated after ALPPS in pig liver cells; then, we identified the orthologous circRNA in humans and pigs to detect their function in liver regeneration. The results showed that loss of circ-0067724 and circ-0016213 could suppress liver cell proliferation. Together, these findings suggest that circ-0067724 and circ-0016213 play an important role in liver cell proliferation, and this may help us to find new strategies to promote liver regeneration.
Development of novel targeted therapies remains the priority in hepatocellular carcinoma (HCC) treatments. Early reports have demonstrated that androgen receptor (AR) plays a suppressive role in HCC ...progression. However, the underlying mechanisms by which AR attenuates HCC development are still elusive, especially under hypoxic conditions. Herein, we demonstrated that AR/circ-LNPEP/miR-532–3p/RAB9A signaling axis was tightly involved in hypoxia-induced cell invasion of HCC cells. AR worked as a transcription factor to reduce circ-LNPEP expression level, which released its sponge potential of miR-532–3p, leading to the downregulation of RAB9A and inhibiting cell invasion of HCC cells. In vitro and in vivo animal model also confirmed that overexpression of circ-LNPEP could reverse the suppressive effect of AR on HCC cell invasion or tumor metastasis. Overall, our study supplements a critical mechanism by which AR suppresses HCC invasion/metastasis under hypoxic conditions, providing compelling rationale to develop novel therapy for better treatments of HCC.
•Circ-LNPEP acts as a novel therapeutic target for HCC.•RAB9A is the downstream of miR-532–3p that sponged by Circ-LNPEP to regulate HCC cell invasion under hypoxia.•Illustrating a new mechanism of androgen receptor regulating HCC cell invasion under hypoxia.
Previous studies have shown that semaphorin-3F (SEMA3F) functions as a tumor suppressor in several tumor types. However, the role of SEMA3F in the metastasis and prognosis of liver hepatocellular ...carcinoma (LIHC) remains unknown. In this study, by performing bioinformatics analysis on the transcriptome profiles from The Cancer Genome Atlas (TCGA), we demonstrated that SEMA3F was significantly upregulated in LIHC tissues, compared with normal controls. Moreover, the expression value of SEMA3F was positively correlated with patients' pathological stages and tumor metastasis, predicting a poor overall survival. Besides, SEMA3F expression level was negatively correlated with its methylation level, but positively correlated with its gene copy number. Differential expression analysis of LIHC samples with high or low SEMA3F expression values suggested that 983 genes were differentially expressed, among which 723 genes were upregulated and 260 genes were downregulated. Furthermore, enrichment analysis of differentially expressed genes revealed that SEMA3F was involved in the activation of focal adhesion pathway, which induced tumor metastasis. Taken together, our results suggested that the oncogenic function of SEMA3F promoted hepatocellular carcinoma metastasis by activating focal adhesion pathway.
The roles of M2 macrophages on promoting tumor progression and chemotherapy resistance have been well studied in many cancers, such as pancreatic cancer, kidney cancer and so on, but its linkage to ...HCC cells still remains unclear. Here we found that M2 macrophages could alter miR-149-5p to increase MMP9 expression in HCC cells and mechanism dissection revealed that miR-149-5p might directly target the 3'UTR of MMP9-mRNA to suppress its translation. The in vivo orthotopic xenografts mouse model with oemiR-149-5p also validated in vitro data. Together, these findings suggest that M2 macrophages may through altering the miR-149-5p to promote HCC progression and targeting the M2 macrophages/miR149-5P/MMP9 signaling may help in the development of the novel therapies to better suppress the HCC progression.
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