Research IndicatorsGraph generated 30 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (8)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: ROCK1 (cancer-related)
Guo D, Li Y, Chen Y, et al.DANCR promotes HCC progression and regulates EMT by sponging miR-27a-3p via ROCK1/LIMK1/COFILIN1 pathway.
Cell Prolif. 2019; 52(4):e12628 [PubMed
] Related Publications
OBJECTIVES: This research aims to verify that the long non-coding RNA differentiation antagonizing nonprotein coding RNA (LncRNA DANCR) could modulate the proliferation and metastasis of hepatocellular carcinoma (HCC), and it thus may work as a novel biomarker to render new orientation for early diagnosis and clinical therapy of HCC.
MATERIALS AND METHODS: Firstly, qRT-PCR was used to detect the expression of genes including LncRNA DANCR and miR-27a-3p. Next, MTT assay, Ethynyldeoxyuridine (EdU) analysis and clone formation assay were used for investigating cell growth and proliferation. Meanwhile, transwell assay and wound healing assay were applied to evaluate the capacity of cell metastasis and motility, respectively. In addition, bioinformatic analysis and dual-luciferase reporter assay were applied to analyse molecular interaction. Next, we conducted immunofluorescence and Western blot for mechanic investigation. Last but not the least, xenograft tumours in nude mice were built by subcutaneously injecting Hep3B cells stably transfected with sh-NC and sh-DANCR to detect proliferation and SMMC-7721 cells stably transfected with sh-NC and sh-DANCR to investigate metastasis.
RESULTS: The results of qRT-PCR and bioinformatic analysis revealed the high expression of DANCR in HCC. DANCR accelerated proliferation and metastasis of HCC cells and the knockdown of DANCR had the opposite effect. Meanwhile, xenograft tumours in sh-DANCR group grow slower and have smaller volumes compared with negative control group. Next, the antineoplastic effect of miR-27a-3p on cell growth and motility of HCC was confirmed. In addition, we clarified that DANCR acted as a ceRNA to decoy miR-27a-3p via mediating ROCK1/LIMK1/COFILIN1 pathway. In the end, we validated that DANCR/miR-27a-3p axis regulates EMT progression by cell immunofluorescence and Western blot.
CONCLUSIONS: In a word, DANCR promotes HCC development and induces EMT by decoying miR-27a-3p to regulate ROCK1/LIMK1/COFILIN1 pathway.
Yu G, Wang Z, Zeng S, et al.Paeoniflorin Inhibits Hepatocyte Growth Factor- (HGF-) Induced Migration and Invasion and Actin Rearrangement via Suppression of c-Met-Mediated RhoA/ROCK Signaling in Glioblastoma.
Biomed Res Int. 2019; 2019:9053295 [PubMed
] Free Access to Full Article Related Publications
Paeoniflorin (PF), as one of the important valid natural compounds of the total glucosides of peony, has displayed a potential effect in cancer prevention and treatment. Aggressive migration and invasion, as an important process, can contribute to tumor progression through infiltrating the surround normal tissue. Actin cytoskeleton rearrangement plays a key role in cells migration and invasion, involving multiple signal pathways. HGF/c-Met signal, as an important couple of oncoprotein, has been demonstrated to regulate actin cytoskeleton rearrangement. In our study, we aim to explore whether paeoniflorin can inhibit migration and invasion and actin cytoskeleton rearrangement via regulation of HGF/c-Met/RhoA/ROCK signal. Various approaches were applied to demonstrate the mechanism of paeoniflorin-mediated anticancer effect, including cell wound healing assay, invasion assay, immunofluorescence staining and transfection, and western blotting. We observed that paeoniflorin inhibited HGF-induced migration and invasion and actin cytoskeleton rearrangement in glioblastoma cells. Furthermore, the inhibition of HGF-induced migration and invasion and actin cytoskeleton rearrangement involved c-Met-mediated RhoA/ROCK signaling in glioblastoma. Thus, our study proved that paeoniflorin could inhibit migration and invasion and actin cytoskeleton rearrangement through inhibition of HGF/c-Met/RhoA/ROCK signaling in glioblastoma, suggesting that paeoniflorin might be a candidate compound to treat glioblastoma.
Liu H, Hou T, Ju W, et al.MicroRNA‑122 downregulates Rho‑associated protein kinase 2 expression and inhibits the proliferation of prostate carcinoma cells.
Mol Med Rep. 2019; 19(5):3882-3888 [PubMed
] Related Publications
MicroRNA‑122 (miR‑122) has been reported to be involved in the pathogenesis of several types of malignancies; however, its role in prostate carcinoma remains unknown. Thus, the current study aimed to investigate the functionality of miR‑122 in prostate carcinoma. Clinical data of 54 patients with prostate carcinoma who were diagnosed and treated in Union Hospital (Wuhan, China) between January 2011 and January 2013 were retrospectively analyzed. The expression levels of miR‑122 and Rho‑associated protein kinase 2 (ROCK2) in prostate tumor and adjacent healthy tissues of patients, as well as in the serum of prostate carcinoma patients and healthy controls, were detected by reverse transcription‑quantitative polymerase chain reaction. Receiver operating characteristic curve and survival curve analyses were used to examine the diagnostic and prognostic values of serum miR‑122 for prostate carcinoma. In addition, miR‑122 mimic was transfected into prostate carcinoma cells, and the effects on cell proliferation and ROCK2 expression were explored by Cell Counting Kit‑8 and western blot assays, respectively. It was observed that miR‑122 was downregulated and ROCK2 was upregulated in tumor tissues as compared with their levels in adjacent healthy tissues. miR‑122 level in the serum was also markedly lower in prostate carcinoma patients in comparison with that in healthy controls. Furthermore, a low serum level of miR‑122 was found to effectively distinguish the prostate carcinoma patients from healthy controls and to be an indicator of poor survival. In prostate carcinoma cells, miR‑122 overexpression inhibited the proliferation and the expression of ROCK2. Taken together, miR‑122 may inhibit the proliferation of prostate carcinoma cells possibly by downregulating ROCK2 expression.
BACKGROUND: Damage-regulated autophagy modulator 2(DRAM2) is associated with autophagy processes. However, the role of DRAM2 in the progression of human neoplasms is still unknown. Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC).
METHODS: Tumor specimens from 259 NSCLC patients were collected and analyzed. Transwell migration, cell cycle analysis, MTT and colony formation assays were performed to determine the effect of DRAM2 overexpression and knockdown on NSCLC-cell migration and proliferation. Western blotting confirmed the expression of DRAM2, p53, and the other involved proteins.
RESULTS: DRAM2 was preferentially upregulated in NSCLC tissues and higher expression of DRAM2 in NSCLC correlated with tumor node metastases stage and lymph node metastasis. Additionally, DRAM2 overexpression promoted cell metastasis and proliferation in vitro, while knockdown of DRAM2 expression yielded opposite result. Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. DRAM2 overexpression also increased proteins CDK4, CyclinD3, and decreased p27 expression, all of which are cell cycle-related factors. Consistently knocked down DRAM2 had the opposite effect. We also found that DRAM2 expression was negatively correlated to p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression. Finally, absence of p53 did not influence the function of DRAM2 in NSCLC, but overexpression of p53 repressed its function.
CONCLUSIONS: DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Therefore, DRAM2 may act as an oncogene in NSCLC and could serve as a prognostic factor and potential target for NSCLC treatment.
Extracellular matrix (ECM)-related adhesion proteins are important in metastasis. Ras suppressor-1 (RSU-1), a suppressor of
Deng R, Zhang J, Chen JlncRNA SNHG1 negatively regulates miRNA‑101‑3p to enhance the expression of ROCK1 and promote cell proliferation, migration and invasion in osteosarcoma.
Int J Mol Med. 2019; 43(3):1157-1166 [PubMed
] Free Access to Full Article Related Publications
Osteosarcoma (OS) is a rare malignant bone tumor that commonly occurs in children and adolescents and causes pain and swelling of the long bones of the legs and arms. Long non‑coding RNA (lncRNA) and micro (mi)RNA‑101 are important in the initialization and progression of OS. However, the mechanism underlying the role of the lncRNA and miRNA‑101 in OS remains to be fully elucidated. In the present study, through reverse transcription‑quantitative polymerase chain reaction analysis, it was first found that the lncRNA SNHG1 was upregulated and miRNA‑101‑3p was downregulated in OS tissues and cell lines. Second, the knockdown of lncRNA SNHG1 induced cell apoptosis and maintained the cell cycle at the G0/G1 phase, which decreased the overall cell viability. Furthermore, according to a dual‑luciferase assay and western blot analysis, miRNA‑101‑3p was found to be a target of the lncRNA SNHG1 in OS, which further regulated the expression of Rho‑associated coiled‑coil‑containing protein kinase 1 (ROCK1). It was found that the phosphoinositide 3‑kinase/ATK pathway was inactivated and that epithelial‑mesenchymal transition was activated in OS cell lines with overexpression of the lncRNA SNHG1. Taken together, in OS cell lines, the lncRNA SNHG1 acted as an oncogene, and miRNA‑101‑3p was considered a tumor suppressor. The lncRNA SNHG1 promoted OS cell proliferation, migration and invasion by downregulating the expression of miRNA‑101‑3p, which enhanced the expression of ROCK1.
Wang W, Du H, Liu H, et al.SMAD specific E3 ubiquitin protein ligase 1 promotes ovarian cancer cell migration and invasion via the activation of the RhoA/ROCK signaling pathway.
Oncol Rep. 2019; 41(1):668-676 [PubMed
] Related Publications
SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) serves a pivotal role in a variety of pathological processes and in tumor cell migration and invasion; however, its functional mechanism in ovarian cancer (OC) remains unknown. Previously, we observed overexpression of SMURF1 in OC tissues. In the present study, the role of SMURF1 in OC metastasis was investigated. The results revealed that SMURF1 was upregulated in OC cell lines of greater aggression than less aggressive cells. Downregulation of SMURF1 significantly inhibited OC cell invasion and migration, whereas upregulation of SMURF1 promoted OC cell invasion and migration. Investigation of the mechanism underlying the effects of SMURF1 in OC revealed that SMURF1 induced OC cell migration and invasion via activation of the Ras homolog family member A/Rho‑associated protein kinase signaling pathway. Further analysis demonstrated that higher levels of SMURF1 expression were associated with shorter overall survival in patients with OC. The findings of the present study indicated that overexpression of SMURF1 may contribute to the malignancy and metastasis of OC. The inhibition of SMURF1 expression may be a promising strategy for the treatment of patients with OC.
Wang A, Zhang Y, Cao PInhibition of BAP31 expression inhibits cervical cancer progression by suppressing metastasis and inducing intrinsic and extrinsic apoptosis.
Biochem Biophys Res Commun. 2019; 508(2):499-506 [PubMed
] Related Publications
Cervical cancer is reported as one of the most lethal types of cancer among female. However, extensive studies of the molecular mechanisms that regulate the progression of cervical cancer are still required. B-cell associated protein (BAP)-31 is a 28-kDa integral membrane protein in the endoplasmic reticulum (ER), playing essential role in modulating various physiological processes. The present study indicated that BAP31 was a novel gene associated with cervical cancer development. Here, we demonstrated that BAP31 was significantly increased in human cervical cancer specimens, which was positively correlated to histological grade of the cancer. BAP31 knockdown suppressed cell proliferation, clonogenic ability and metastasis-associated traits in vitro, as well as carcinogenesis and pulmonary metastasis in vivo. Further studies indicated that the expression levels of transforming growth factor (TGF)-β1, matrix metalloproteinase (MMP)-2, MMP-9, Rho-associated protein kinase 1 (ROCK1), α-smooth muscle actin (α-SMA), Vimentin and N-cadherin were markedly reduced by BAP31 knockdown in cervical cancer cells. In addition, intrinsic and extrinsic apoptosis was significantly induced in BAP31 knockdown cells, as evidenced by the increased expression of cleaved Caspase-8/-9/-3 and poly (ADP-ribose) polymerases (PARP). Notably, suppressing the activities of Caspase-8/-9 and -3 obviously diminished BAP31 silence-triggered apoptosis. Together, these findings highlighted an essential role for BAP31 in the modulation of tumorigenesis and metastatic potential of cervical cancer, and demonstrated a promising application of BAP31 in cancer prevention.
Luo J, Lou Z, Zheng JTargeted regulation by ROCK2 on bladder carcinoma via Wnt signaling under hypoxia.
Cancer Biomark. 2019; 24(1):109-116 [PubMed
] Related Publications
Bladder cancer is frequently occurred in urinary system and has complicated pathogenesis factors including both genetics and environmental factors that have not been fully illustrated. Hypoxia can further induce tumor progression. ROCK2 has abnormal expression in various tumors but its expression or functional role in bladder cancer have not been illustrated. In vitro cultured bladder cancer cell line T24 was randomly assigned into control group, hypoxia group (prepared under hypoxic culture), and ROCK2 siRNA group (transfected with ROCK2 siRNA after hypoxia treatment). Real-time PCR and Western bot measured ROCK2 expression. MTT assay tested cell proliferation, and cell migration was quantified. Cell apoptosis was measured by caspase3 activity assay kit and Transwell chamber measured cell migration. Western blot quantified expressional change of HIF-1α and E-cadherin, and Wnt signal pathway proteins including Wnt4, and β-catenin. ROCK2 is up-regulated in bladder cancer T24 cells under hypoxia, and can facilitate cell proliferation, migration and invasion, inhibited Caspase3 activity, enhanced HIF-1α expression, decreased E-cadherin expression, and up-regulated Wnt4 and β-catenin (p< 0.05 comparing to hypoxia group). Under hypoxia conditions, ROCK2 can facilitate apoptosis of bladder cancer cells via modulating Wnt signal pathway, inhibit cell proliferation, migration, invasion or formation of epithelial mesenchymal transition (EMT).
Cutaneous melanoma is very aggressive and results in high mortality rates for cancer patients. Determining molecular targets is important for developing novel therapies for cutaneous melanoma. Cell division cycle associated 8 (CDCA8) is a putative oncogene that is upregulated in multiple types of cancer. The present study aimed to examine the role of CDCA8 in cutaneous melanoma, with a focus on the association of its expression to prognosis and metastasis. First, the mRNA expression of CDCA8 in cutaneous melanoma tissues was investigated using the ONCOMINE and Gene Expression Omnibus (GEO) databases. Furthermore, the relationship between the expression of CDCA8 and cutaneous melanoma patient survival was analyzed using a Kaplan‑Meier plot and Log Rank test. In addition, the effects of CDCA8 on proliferation, migration and invasion of cutaneous melanoma cell lines were investigated using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR), Cell Counting kit‑8, colony formation assay, wound healing and Matrigel assay. Finally, the expression levels of key proteins related to the Rho‑associated coiled‑coil‑containing protein kinase (ROCK) signaling pathway were measured by western blot assay. The results demonstrated that CDCA8 was overexpressed in cutaneous melanoma tissues and cells lines compared with normal tissues, and high expression of CDCA8 was significantly associated with poorer prognosis in patients with cutaneous melanoma. In in vitro experiments, CDCA8 knockdown inhibited A375 and MV3 cell proliferation, migration and invasion. In addition, CDCA8 knockdown reduced the phosphorylation levels of ROCK1 and myosin light chain, two downstream effector proteins of the ROCK pathway. In summary, the present findings suggested that CDCA8 may be a promising therapeutic target for the treatment of cutaneous melanoma.
The lack of representative nasopharyngeal carcinoma (NPC) models has seriously hampered research on EBV carcinogenesis and preclinical studies in NPC. Here we report the successful growth of five NPC patient-derived xenografts (PDXs) from fifty-eight attempts of transplantation of NPC specimens into NOD/SCID mice. The take rates for primary and recurrent NPC are 4.9% and 17.6%, respectively. Successful establishment of a new EBV-positive NPC cell line, NPC43, is achieved directly from patient NPC tissues by including Rho-associated coiled-coil containing kinases inhibitor (Y-27632) in culture medium. Spontaneous lytic reactivation of EBV can be observed in NPC43 upon withdrawal of Y-27632. Whole-exome sequencing (WES) reveals a close similarity in mutational profiles of these NPC PDXs with their corresponding patient NPC. Whole-genome sequencing (WGS) further delineates the genomic landscape and sequences of EBV genomes in these newly established NPC models, which supports their potential use in future studies of NPC.
In recent years, long noncoding RNAs (lncRNAs) have been reported to have significant regulating effect in human cancer development. Previous studies suggested that dysregulation of lncRNA 441178 (LOC441178) is possibly associated with oral squamous cell carcinoma (OSCC). The postoperative survival time was significantly prolonged in the high-grade OSCC patients with high LOC441178 expression compared with those with low LOC441178 expression, which indicated that LOC441178 may act as a prognostic marker and as a potential tumor suppressor for OSCC. However, the biological molecular mechanisms behind these phenomena remain almost unknown. Here, our studies revealed that LOC441178 suppressed the invasion and migration of squamous carcinoma cells (SCCs). Furthermore, we found that rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) is one of the functionally relevant targets of LOC441178 in squamous cells, which is negatively correlated with LOC441178 in tumor tissues from OSCC patients. In conclusion, our findings demonstrated the inhibition effect of LOC441178 on tumor in OSCC and might have potential implications for OSCC gene therapy. In conclusion, these results suggest that LOC441178 could represent a prognostic indicator for OSCC and be a new target for the diagnosis and treatment of OSCC.
Mammalian STE20-like kinase 1 (Mst1) is well recognized as a major tumor suppressor in cancer development, growth, metabolic reprogramming, metastasis, cell death and recurrence. However, the roles of Mst1 in non-small cell lung cancer (NSCLC) A549 cell phenotypic alterations remain to be elucidated. The present study aimed to explore the functional role and underlying mechanisms of Mst1 with regards to A549 cell proliferation, migration and apoptosis; this study focused on mitochondrial homeostasis and Rho-associated coiled-coil containing protein kinase 1 (ROCK1)/F‑actin pathways. The results demonstrated that Mst1 was downregulated in A549 cells compared with in a normal pulmonary epithelial cell line. Subsequently, overexpression of Mst1 in A549 cells reduced cell viability and promoted cell apoptosis. Furthermore, overexpression of Mst1 suppressed A549 cell proliferation and migration. At the molecular level, the reintroduction of Mst1 in A549 cells led to activation of mitochondrial apoptosis, as evidenced by a reduction in mitochondrial potential, overproduction of ROS, cytochrome c release from the mitochondria into the nucleus, and upregulation of pro-apoptotic protein expression. In addition, Mst1 overexpression was closely associated with impaired mitochondrial respiratory function and suppressed cellular energy metabolism. Functional studies illustrated that Mst1 overexpression activated ROCK1/F-actin pathways, which highly regulate mitochondrial function. Inhibition of ROCK1/F-actin pathways in A549 cells sustained mitochondrial homeostasis, alleviated caspase-9-dependent mitochondrial apoptosis, enhanced cancer cell migration and increased cell proliferation. In conclusion, these data firmly established the regulatory role of Mst1 in NSCLC A549 cell survival via the modulation of ROCK1/F-actin pathways, which may provide opportunities for novel treatment modalities in clinical practice.
BACKGROUND: Approximately half of the documented increases in differentiated thyroid carcinoma is due to identification of papillary thyroid microcarcinomas (PTMCs). Knowing whether PTMC is aggressive is required for proper treatment, but until now, there has been no method for assessing these traits and understanding the underlying mechanisms for aggressiveness.
METHODS: We performed whole-exome sequencing of 16 PTMCs and matched normal thyroid tissues and GO/KEGG analysis to study genetic alterations and biological consequences associated with aggressive PTMCs, and then sequenced these genes using a next-generation gene-panel approach in an additional 70 PTMC samples including aggressive (n = 50) and non-aggressive (n = 20) groups.
RESULTS: We identified 254 somatic mutations of 234 genes, for which 178 mutations in 168 genes were found in the aggressive group, and 76 mutations in 74 genes were found in the non-aggressive group. Several recurrent mutations in BRAF, VCAN, ALDH1L1, and MUC5B were identified, and many novel but infrequent mutations in other genes were also found. The aggressive cohort had more mutational burdens than the non-aggressive group (P = 0.004). Nonsynonymous mutations of 13 genes (MUC5B, TNN, SSPO, PPFIA1, PCDHGA2, ITGA8, ITGA4, DCHS1, CRNN, ROCK1, RELN, LAMC2, and AEBP1) were involved in cell adhesion, and these were only present in the aggressive group. Targeted sequencing of these genes revealed significant enrichment in the aggressive group (P = 0.000004).
CONCLUSION: PTC may have evolved from PTMC due to sharing similar gene mutations, and the accumulation of such mutations promoted the aggressiveness of PTMC. Gene mutants associated with cell adhesion may be used to predict PTMC aggressiveness and allow more selective treatment.
Ovarian cancer (OC) is the leading cause of death among women with gynecologic malignant diseases, however, the molecular mechanism of ovarian cancer is not well defined. Previous studies have found that RNA binding protein Lin28A is a key factor of maintain the pluripotency of stem cells, and it is positively correlated with the degree of several cancers (breast, prostate, liver cancer, etc). Our previous study shows that Lin28A is highly expressed in OC tissues and is involved in the regulation of OC cell biological behavior. In this study, we confirmed that high expression of Lin28A promoted the survival, invasion, metastasis, and inhibited the apoptosis of OC cells. Lin28A interacts with Rho associated coiled-coil containing protein kinase2 (ROCK2) but not ROCK1 and upregulates the expression of ROCK2 in OC cells. The binding sites of each other were identified by truncated mutations and Immuno-precipitaion (IP) assay. After knock down of ROCK2 in cells with high expression of Lin28A, the survival, invasion, metastasis was significantly inhibited and early apoptosis was increased in OC cells and OC xenograft in nude mice. Our experimental data also showed that knock down of ROCK2 but not ROCK1 inhibited the invasion by decreasing the expression of N-cadherin, Slug, β-catenin and increasing ZO-1 expression. Simultaneously, knock down of ROCK2 induced cell apoptosis by increasing cleaved Caspase-9,cleaved Caspase-7, and cleaved Caspase-3. Taken together, Lin28A regulated the biological behaviors in OC cells through ROCK2 and the interaction of Lin28A/ROCK2 may be a new target for diagnosis and gene therapy of OC.
Epithelial barrier maintenance and regulation requires an intact perijunctional actomyosin ring underneath the cell-cell junctions. By searching for known factors affecting the actin cytoskeleton, we identified Krev interaction trapped protein 1 (KRIT1) as a major regulator for epithelial barrier function through multiple mechanisms. KRIT1 is expressed in both small intestinal and colonic epithelium, and KRIT1 knockdown in differentiated Caco-2 intestinal epithelium decreases epithelial barrier function and increases cation selectivity. KRIT1 knockdown abolished Rho-associated protein kinase-induced and myosin II motor inhibitor-induced barrier loss by limiting both small and large molecule permeability but did not affect myosin light chain kinase-induced increases in epithelial barrier function. These data suggest that KRIT1 participates in Rho-associated protein kinase- and myosin II motor-dependent (but not myosin light chain kinase-dependent) epithelial barrier regulation. KRIT1 knockdown exacerbated low-dose TNF-induced barrier loss, along with increased cleaved caspase-3 production. Both events are blocked by pan-caspase inhibition, indicating that KRIT1 regulates TNF-induced barrier loss through limiting epithelial apoptosis. These data indicate that KRIT1 controls epithelial barrier maintenance and regulation through multiple pathways, suggesting that KRIT1 mutation in cerebral cavernous malformation disease may alter epithelial function and affect human health.-Wang, Y., Li, Y., Zou, J., Polster, S. P., Lightle, R., Moore, T., Dimaano, M., He, T.-C., Weber, C. R., Awad, I. A., Shen, L. The cerebral cavernous malformation disease causing gene KRIT1 participates in intestinal epithelial barrier maintenance and regulation.
Gao S, Chen J, Wang Y, et al.MiR-592 suppresses the development of glioma by regulating Rho-associated protein kinase.
Neuroreport. 2018; 29(16):1391-1399 [PubMed
] Related Publications
MicroRNAs are a class of small noncoding RNAs that regulate the translation of target mRNA transcripts. MiR-592 has been considered to play important roles in the initiation and progression of cancer by targeting various molecules in several human cancers, but its role in glioma has not been explored. This study aims to explore the suppressive mechanism of miR-592 in the regulation of glioma development, an effect that is crucial for the further exploration of miR-592 as a novel therapeutic target for glioma. Our results proved that the expression of miR-592 was lower and the expression of Rho-associated protein kinase (ROCK1) was higher in glioma tissue than in adjacent tissue and that lower miR-592 expression was associated negatively with ROCK1 expression. Then, we showed that miR-592 was downregulated in glioma and could suppress the growth of the glioma cell lines U87 and U251. ROCK1, which is a known oncogene, was identified as a direct target of miR-592. A luciferase reporter assay indicated that miR-592 regulates ROCK1 expression through binding to its 3'-UTR. Furthermore, our results showed that miR-592 targets the ROCK1 transcript and suppresses glioma cell growth and invasive growth, thereby providing a potential therapeutic target for glioma treatment.
Rho-associated protein kinase (ROCK) plays crucial roles in the proliferation and migration of different types of cells. ROCK inhibitor Y-27632 was previously reported to inhibit melanoma cell growth, and ROCK signaling was suggested to be a therapeutic target for treating melanoma. However, the negative effect of Y-27632 on melanoma cells was mainly seen in studies on murine B16 melanoma cells. Here, we reported that ROCK inhibitor actually promoted human melanoma cell growth and migration in vitro. Y-27632 increased the growth and migration of BRAF-mutated melanoma cells but had a negative effect on wild-type melanoma cells or primary melanocytes. We discovered that Y-27632 enhanced the growth of BRAF-mutated melanoma cells through increased ATK and ERK activity. The in vivo study further confirmed the in vitro finding. These data suggested that the effect of ROCK inhibitor on melanoma cells is cell-context dependent, and the application of ROCK inhibitor in the treatment of melanoma requires further study.
Wang Z, Wang Z, Liu J, Yang HLong non-coding RNA SNHG5 sponges miR-26a to promote the tumorigenesis of osteosarcoma by targeting ROCK1.
Biomed Pharmacother. 2018; 107:598-605 [PubMed
] Related Publications
BACKGROUND: Osteosarcoma (OS) is one of the most common invasive malignancies of the bone. The long non-coding RNA (lncRNA) SNHG5 (small nucleolar RNA host gene 5) has been consistently shown to be involved in many cancers, although its precise function in osteosarcoma remains poorly understood. In this study, we investigated the role of SNHG5 in OS progression and the underlying mechanism.
METHODS: SNHG5 expression in 32 OS tissues and 4 OS cell lines was measured by quantitative real-time PCR (qRT-PCR). Migration, invasion, proliferation and cell cycle profiles were analyzed by established assays to determine the biological functions of SNHG5 and miR-26a in OS cells. The binding sites of miR-26a in SNHG5 and ROCK1 were predicted by the RNAhybrid 2.2 program. Luciferase reporter assay was then used to validate the direct targeting of SNHG5 with miR-26a and of Rho-associated coiled coil-containing protein kinase 1 (ROCK1) with miR-26a. The effect of SNHG5 on the ROCK signaling pathway was assessed by western blotting.
RESULTS: Elevated expression of SNHG5 was correlated with poor clinical outcome and prognosis in OS patients. SNHG5 functioned as a sponge for miR-26a and promoted proliferation, invasion and migration, and accelerated G1 to S phase transition in OS cells. SNHG5 functioned as a competing endogenous RNA (ceRNA) for miR-26a and activated the ROCK signaling pathway through the miR-26a-ROCK1 axis.
CONCLUSION: SNHG5 acts as an oncogene in OS via the SNHG5-miR-26a-ROCK1 axis and is therefore a potential novel therapeutic target for OS treatment.
Liu W, Zhang Q, Tang Q, et al.Lycorine inhibits cell proliferation and migration by inhibiting ROCK1/cofilin‑induced actin dynamics in HepG2 hepatoblastoma cells.
Oncol Rep. 2018; 40(4):2298-2306 [PubMed
] Related Publications
Lycorine, a natural alkaloid extracted from the Amaryllidaceae plant family, has been reported to exhibit anti‑cancer effects in various types of cancer cells. However, the molecular mechanisms through which lycorine exhibits anti‑hepatoblastoma activity are unclear. In the present study, the inhibitory effects of lycorine on the proliferation and migration of HepG2 hepatoblastoma cells were investigated. Lycorine inhibited the proliferation of HepG2 cells in a dose‑dependent manner by inducing cell cycle arrest at the G2/M phase, via downregulation of cyclin A, cyclin B1 and cyclin dependent kinase 1. Additionally, wound healing and Transwell assays revealed that treatment with lycorine resulted in a decrease in the migratory ability of HepG2 cells. Also, treatment with lycorine decreased the expression levels of matrix metalloproteinase (MMP)‑9 and MMP‑2. Furthermore, lycorine induced the cleavage/activation of Rho associated coiled‑coil containing protein kinase 1 (ROCK1) and the downregulation of cofilin, accompanied by an increase in polymerized filamentous actin and a loss of depolymerized globular actin. Furthermore, pre‑incubation of cells with Y‑27632, a specific ROCK1 inhibitor, markedly attenuated lycorine‑induced anti‑proliferative and anti‑migration effects. Taken together, the results demonstrated that lycorine inhibited the proliferation and migration of HepG2 cells by suppressing ROCK1/cofilin‑induced actin dynamics, which suggests that lycorine has the potential to be developed into a novel drug for hepatoblastoma treatment.
Zheng Y, Xiang L, Chen M, Xiang CMicroRNA‑130a inhibits the proliferation, migration and invasive ability of hepatocellular carcinoma cells by downregulating Rho‑kinase 2.
Mol Med Rep. 2018; 18(3):3077-3084 [PubMed
] Related Publications
MicroRNA‑130a (miR‑130a) has been reported to be downregulated in hepatocellular carcinoma (HCC). However, the roles and underlying tumor‑suppressive mechanisms of miR‑130a in the pathogenesis of HCC remain unclear. In the current study, reduced expression of miR‑130a was observed in tumor tissues of patients with HCC in addition to in four HCC cell lines, BEL‑7402, MHCC97H, HepG2 and Huh7. Results of methyl thiazolyl tetrazolium (MTT) assays identified decreased growth rates of MHCC97H and HepG2 cells transfected with miR‑130a mimics. The in vitro colony formation assays demonstrated that the number of colonies formed by cells transfected with miR‑130a mimics and cells transfected with miR‑130a inhibitors was lower and higher, respectively, than that formed by the cells transfected with miR‑negative control. In addition, it was identified that overexpression of miR‑130a reduced the migration and invasiveness of MHCC97H and HepG2 cells. Luciferase reporter assays demonstrated that miR‑130a directly targeted the 3'‑untranslated region of Rho‑kinase 2 (ROCK2) mRNA. Northern and western blot analyses indicated that miR‑130a could modulate the mRNA and protein expression of ROCK2. Additionally, small‑interfering RNA‑mediated knockdown of ROCK2 decreased the proliferation, migration and invasiveness of MHCC97H and HepG2 cells. Overall, these observation suggest that miR‑130a is a regulator of ROCK2 and can inhibit proliferation, migration and invasive ability of HCC cells, at least in part, by suppressing the expression of ROCK2. The current study provides further insight into the molecular mechanisms of HCC pathogenesis and suggests a new potential biotarget for HCC treatment.
Li X, He J, Shao M, et al.Downregulation of miR-218-5p promotes invasion of oral squamous cell carcinoma cells via activation of CD44-ROCK signaling.
Biomed Pharmacother. 2018; 106:646-654 [PubMed
] Related Publications
The invasion front of oral squamous cell carcinoma (OSCC) harbors the most aggressive cells of the tumor and is critical for cancer invasion and metastasis. MicroRNAs (miRNAs) play important roles in OSCC progression. In this study, we modelled the OSCC invasion front on a microfluidic chip, and investigated differences in miRNA profiles between cells in the invasion front and those in the tumor mass by small RNA sequencing. We found that miR-218-5p was downregulated in invasion front cells and negatively regulates OSCC invasiveness by targeting the CD44-ROCK pathway. Thus, miR-218-5p may serve as a useful therapeutic target for OSCC. Moreover, invasion front cell isolation based-on microfluidic technology provided a useful strategy for cancer invasion study.
Chen X, Zhang S, Wang Z, et al.Supervillin promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma in hypoxia via activation of the RhoA/ROCK-ERK/p38 pathway.
J Exp Clin Cancer Res. 2018; 37(1):128 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and metastasis is the leading cause of death associated with HCC. Hypoxia triggers the epithelial-mesenchymal transition (EMT) of cancer cells, which enhances their malignant character and elevates metastatic risk. Supervillin associates tightly with the membrane and cytoskeleton, promoting cell motility, invasiveness, and cell survival. However, the roles of supervillin in HCC metastasis remain unclear.
METHODS: Tissue microarray technology was used to immunohistochemically stain for supervillin antibody in 173 HCC tissue specimens and expression levels correlated with the clinicopathological variables. Tumor cell motility and invasiveness, as well as changes in the mRNA expression levels of genes associated with cancer cell EMT, were investigated. The relationship between supervillin and Rho GTPases was examined using Co-IP and GST pull-down.
RESULTS: Hypoxia-induced upregulation of supervillin promoted cancer cell migration and invasion via the activation of the ERK/p38 pathway downstream of RhoA/ROCK signaling. Furthermore, supervillin regulated the expression of EMT genes during hypoxia and accelerated the metastasis of HCC in vivo.
CONCLUSIONS: Hypoxia-induced increase in supervillin expression is a significant and independent predictor of cancer metastasis, which leads to poor survival in HCC patients. Our results suggest that supervillin may be a candidate prognostic factor for HCC and a valuable target for therapy.
Cerebral cavernous malformations (CCMs) are clusters of dilated capillaries that affect around 0.5% of the population. CCMs exist in two forms, sporadic and familial. Mutations in three documented genes, KRIT1(CCM1), CCM2, and PDCD10(CCM3), cause the autosomal dominant form of the disease, and somatic mutations in these same genes underlie lesion development in the brain. Murine models with constitutive or induced loss of respective genes have been applied to study disease pathobiology and therapeutic manipulations. We aimed to analyze the phenotypic characteristic of two main groups of models, the chronic heterozygous models with sensitizers promoting genetic instability, and the acute neonatal induced homozygous knockout model. Acute model mice harbored a higher lesion burden than chronic models, more localized in the hindbrain, and largely lacking iron deposition and inflammatory cell infiltrate. The chronic model mice showed a lower lesion burden localized throughout the brain, with significantly greater perilesional iron deposition, immune B- and T-cell infiltration, and less frequent junctional protein immunopositive endothelial cells. Lesional endothelial cells in both models expressed similar phosphorylated myosin light chain immunopositivity indicating Rho-associated protein kinase activity. These data suggest that acute models are better suited to study the initial formation of the lesion, while the chronic models better reflect lesion maturation, hemorrhage, and inflammatory response, relevant pathobiologic features of the human disease.
Kai D, Yannian L, Yitian C, et al.Circular RNA HIPK3 promotes gallbladder cancer cell growth by sponging microRNA-124.
Biochem Biophys Res Commun. 2018; 503(2):863-869 [PubMed
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Recent studies have implied that circHIPK3, an abundant circular RNA (circRNA), participates in tumorigenesis and cancer progression. Its expression and potential functions in human gallbladder cancer were examined in this study. We show that circHIPK3 is upregulated in human gallbladder cancer cells. But its level is low in gallbladder epithelial cells. circHIPK3 silencing by targeted siRNA potently inhibited survival and proliferation of established and primary human gallbladder cancer cells, while inducing cell apoptosis. Conversely, ectopic over-expression of circHIPK3 can further promote cancer cell proliferation. In gallbladder cancer cells, circHIPK3 sponged the tumor-suppressive microRNA-124 (miR-124) to sequester and inhibit its activity, thereby leading to increased expression of miR-124 targets, including ROCK1 (rho-associated protein kinase 1) and CDK6 (rho-associated protein kinase). Ectopic over-expression of miR-124 b y a lentiviral vector mimicked and abolished actions by circHIPK3 siRNA in gallbladder cancer cells. At last, we show that circHIPK3 is upregulated in human gallbladder cancer tissues, which is correlated with miR-124 downregulation and ROCK1-CDK6 upregulation. Together, we conclude that circHIPK3 promotes gallbladder cancer cell growth possibly by sponging miR-124. The over-expressed circHIPK3 could be a novel therapeutic target and diagnosis marker of human gallbladder cancer.
Wang ZH, Zhan-Sheng HCatalpol inhibits migration and induces apoptosis in gastric cancer cells and in athymic nude mice.
Biomed Pharmacother. 2018; 103:1708-1719 [PubMed
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Gastric cancer is one of the leading factors, causing tumor-associated death worldwide. However, due to the limited therapeutic strategies in inhibition of gastric cancer, further studies are still required to develop effective treatments. In the present study, we attempted to explore the effects of catalpol, extracted from a traditional Chinese herb Rehmannia glutinosa, on gastric cancer progression in cells and in xenograft nude mice. The results indicated that catalpol dose-dependently reduced the proliferation of cancer cells. The migrated cells were also decreased with catalpol treatment, as evidenced by the down-regulated expressions of matrix metalloproteinase-2 (MMP-2), alpha-smooth muscle actin (α-SMA), Ras homolog gene family, member A (RhoA), Rho kinase 1 (ROCK1) and N-cadherin. Further, catalpol induced apoptosis in gastric cancer cells. Apoptosis-related markers including cleaved Caspase-3 and PARP were highly expressed in catalpol-treated cells. However, the cells with pre-treatment of caspases inhibitor reversed catalpol-induced apoptosis. Further, catalpol also enhanced reactive oxygen species (ROS) generation in gastric cancer cells, which was eliminated by N-acetylcystein (NAC) pre-incubation, an important ROS scavenger. Of note, catalpol potentiated the anti-cancer effects of cisplatin (DDP) in suppressing gastric cancer cells. In vivo, catalpol prevented the tumor growth in xenograft nude mice, while no significant difference was observed in body weight. The immunohistochemical analysis showed that catalpol increased the number of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive cells, whereas decreased the number of KI-67-positive cells. Together, the results above indicated that catalpol has a potential value in treating gastric cancer.
Mounting evidence indicates that microRNAs play important roles in the development of various cancers. Aberrant expression of microRNA-199a-5p has been frequently reported in cancer studies; however, the mechanistic details of the role of microRNA-199a-5p in colorectal cancer still remain unclear. Our study aimed to explore the role of microRNA-199a-5p in colorectal cancer cells by targeting Rho-associated coiled coil-containing protein kinase 1. Here, we showed that microRNA-199a-5p was significantly downregulated in colorectal cancer cell lines and tissue samples and was associated with a poor prognostic phenotype. MicroRNA-199a-5p suppressed colorectal cancer cell proliferation, migration, and invasion and induced cell apoptosis. Moreover, we identified Rho-associated coiled coil-containing protein kinase 1 as the direct target of microRNA-199a-5p using luciferase and Western blot assays. Importantly, Rho-associated coiled coil-containing protein kinase 1 overexpression rescued the microRNA-199a-5p-induced suppression of proliferation, migration, and invasion of colorectal cancer cells. Furthermore, the overexpression of microRNA-199a-5p inhibited tumor growth and metastasis by inactivating the phosphoinositide 3-kinase/AKT and Janus kinase 1/signal transducing activator of transcription signaling pathways through downregulation of Rho-associated coiled coil-containing protein kinase 1. Altogether, microRNA-199a-5p/Rho-associated coiled coil-containing protein kinase 1 may be a potential therapeutic target for colorectal cancer therapy.
Long non-coding RNA (lncRNA) are extensively involved in various malignant tumors, including ovarian cancer (OC). In the present study, we focused on the expression and function of nuclear enriched abundant transcript 1 (NEAT1) in OC cells' metastasis. We demonstrated that NEAT1 was upregulated in OC tissue specimens and cell lines. In addition, we revealed that depression of NEAT1 inhibited OC cells' metastasis and the expression of Rho associated coiled-coil containing protein kinase 1 (ROCK1), which is a metastasis-related gene. Using online predictive software and a series of luciferase assays, we demonstrated that both NEAT1 and ROCK1 were the targets of microRNA-382-3p (miR-382-3p) and share similar microRNA responding elements (MRE). Furthermore, we illustrated that NEAT1 and miR-382-3p inhibited each other in a reciprocal manner. Finally, through antisense experiments we demonstrated that NEAT1 promoted ROCK1-mediated metastasis by functioning as a ceRNA of miR-382-3p. In summary, the findings of this study revealed that NEAT1 promoted OC cells' metastasis through regulating the miR-382-3p/ROCK1 axial. The present study might provide a new target for treating OC.
Rondon AMR, de Almeida VH, Gomes T, et al.Tissue factor mediates microvesicles shedding from MDA-MB-231 breast cancer cells.
Biochem Biophys Res Commun. 2018; 502(1):137-144 [PubMed
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Extracellular vesicles, such as microvesicles (MVs), were identified as important players in tumor progression and acquisition of an aggressive phenotype. Tissue factor (TF) is a transmembrane protein that initiates the blood coagulation cascade. In tumor cells, TF has been associated with aggressiveness and cancer progression. Previous studies demonstrate that TF is incorporated into MVs secreted by tumor cells; however, it is unknown whether TF is actively involved in the release of MVs. Here, we investigated the influence of TF expression on the release of MVs. TF silencing was achieved through CRISPR/Cas9 approaches in the human breast cancer cell line, MDA-MB-231. TF knockout in MDA-MB-231 cells efficiently reduced TF-dependent signaling and procoagulant activity. Remarkably, silencing of TF caused a significant decrease in the number of MVs released by MDA-MB-231 cells. We also observed an increase in actin-positive membrane projections in TF knockout cells and a reduction in RhoA expression when compared to TF-expressing cells. Treatment of MDA-MB-231 cells with the RhoA-ROCK signaling pathway inhibitor, fasudil, significantly reduced the release of MVs. Taken together, our results suggest a novel and relevant role for TF in tumor biology by playing an active role in the MVs secretion.