Gene Summary

Gene:ROCK1; Rho associated coiled-coil containing protein kinase 1
Aliases: ROCK-I, P160ROCK
Summary:This gene encodes a protein serine/threonine kinase that is activated when bound to the GTP-bound form of Rho. The small GTPase Rho regulates formation of focal adhesions and stress fibers of fibroblasts, as well as adhesion and aggregation of platelets and lymphocytes by shuttling between the inactive GDP-bound form and the active GTP-bound form. Rho is also essential in cytokinesis and plays a role in transcriptional activation by serum response factor. This protein, a downstream effector of Rho, phosphorylates and activates LIM kinase, which in turn, phosphorylates cofilin, inhibiting its actin-depolymerizing activity. A pseudogene, related to this gene, is also located on chromosome 18. [provided by RefSeq, Aug 2015]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:rho-associated protein kinase 1
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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).

Latest Publications: ROCK1 (cancer-related)

Chang CD, Lin PY, Hsu JL, Shih WL
Ursolic Acid Suppresses Hepatitis B Virus X Protein-mediated Autophagy and Chemotherapeutic Drug Resistance.
Anticancer Res. 2016; 36(10):5097-5107 [PubMed] Related Publications
Hepatitis B virus X (HBx) protein is a multifunctional oncoprotein that affects diverse cell activities via regulation of various host cell signaling pathways. The current investigation demonstrated that ursolic acid (UA), a pentacyclic triterpenoid, protected hepatoma cells and reduced HBx-mediated autophagy through modulation of Ras homolog gene family member A (RhoA). Low-level ectopic HBx expression in Huh7 cells induced more significant autophagosome formation than high-level HBx expression. HBx activated beclin-1 promoter and enhanced the beclin-1 protein expression under low HBx expression. Transcription factor AP-1 played an essential function in HBx-mediated beclin-1 promoter activation. Inhibition of RhoA and its downstream effector Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) alleviated HBx-mediated autophagy significantly. Transiently-expressed HBx elicited an increased RhoA-GTP level, as well as phospho-ROCK1 transient accumulation. Utilization of transactivation-deficient HBx demonstrated that the transactivation activity of HBx is required for autophagy induction. Furthermore, UA suppressed HBx-mediated RhoA activation, beclin-1 promoter activation and subsequent autophagy induction, while, most importantly, reversed HBx-induced anti-cancer drug resistance.

Zhou L, Xu Z, Ren X, et al.
MicroRNA-124 (MiR-124) Inhibits Cell Proliferation, Metastasis and Invasion in Colorectal Cancer by Downregulating Rho-Associated Protein Kinase 1(ROCK1).
Cell Physiol Biochem. 2016; 38(5):1785-95 [PubMed] Related Publications
BACKGROUND/AIMS: MiR-124 inhibits neoplastic transformation, cell proliferation, and metastasis and downregulates Rho-associated protein kinase (ROCK1) in Colorectal Cancer (CRC). The aim of this study was to further investigate the roles and interactions of ROCK1 and miR-124 and the effects of knockdown of ROCK1and MiR-124 in human Colorectal Cancer (CRC).
METHODS: Three Colorectal cancer cell lines (HCT116, HT29 and SW620) and one Human Colonic Mucosa Epithelial cell line (NCM460) were studied. The protein expression of ROCK1 was examined by Western-blot and qRT-PCR were performed to examine the expression levels of ROCK1 mRNA and miR-124. Furthermore, We performed transfection of cancer cell line (SW620) with pre-miR-124(mimics), anti-miR-124(inhibitor), ROCK1 siRNA and the control, then observed the affects of ROCK1 protein expression by westen-blot, cell proliferation by EDU (5-ethynyl-2'deoxyuridine assay) and expression levels of ROCK1mRNA by qRT-PCR . A soft agar formation assay, Migration and invasion assays were used to determine the effect of regulation of miR-124 and ROCK1, and survivin on the transformation and invasion capability of colorectal cancer cell.
RESULTS: MiR-124 expression was significantly downregulated in CRC cell lines compare to normal (P < 0.05). In contrast, ROCK1 protein expression was significantly increased in CRC cell lines compared to the normal (P < 0.05), whereas the gene (ROCK1mRNA) expression remained unaltered (P > 0.05). ROCK1 mRNA was unaltered in cells transfected with miR-124 mimic and miR-124 inhibitor, compared to normal controls. There was a significant reduction in ROCK1 protein in cells transfected with miR-124 mimic and a significant increase in cells transfected with miR-124 inhibitor (P < 0.05). Cell proliferation, transformation and invasion of cells transfected with miR-124 inhibitor were significantly increased compared to those in normal controls (P<0.05). However, cell proliferation, transformation and invasion of cells transfected with ROCK1 siRNA were significantly decreased compared to control (P < 0.05).
CONCLUSIONS: In conclusion, our results demonstrated that miR-124 not only promoted cancer cell hyperplasia and significantly associated with CRC metastasis and progression, but also downregulated ROCK1 protein expression. More importantly, increased ROCK1 expression or inhibited miR-124 expression may constitute effective new therapeutic strategies for the treatment of renal cancer in the future.

Dyberg C, Papachristou P, Haug BH, et al.
Planar cell polarity gene expression correlates with tumor cell viability and prognostic outcome in neuroblastoma.
BMC Cancer. 2016; 16:259 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The non-canonical Wnt/Planar cell polarity (PCP) signaling pathway is a major player in cell migration during embryonal development and has recently been implicated in tumorigenesis.
METHODS: Transfections with cDNA plasmids or siRNA were used to increase and suppress Prickle1 and Vangl2 expression in neuroblastoma cells and in non-tumorigenic cells. Cell viability was measured by trypan blue exclusion and protein expression was determined with western blotting. Transcriptional activity was studied with luciferase reporter assay and mRNA expression with real-time RT-PCR. Immunofluorescence stainings were used to study the effects of Vangl2 overexpression in non-tumorigenic embryonic cells. Statistical significance was tested with t-test or one-way ANOVA.
RESULTS: Here we show that high expression of the PCP core genes Prickle1 and Vangl2 is associated with low-risk neuroblastoma, suppression of neuroblastoma cell growth and decreased Wnt/β-catenin signaling. Inhibition of Rho-associated kinases (ROCKs) that are important in mediating non-canonical Wnt signaling resulted in increased expression of Prickle1 and inhibition of β-catenin activity in neuroblastoma cells. In contrast, overexpression of Vangl2 in MYC immortalized neural stem cells induced accumulation of active β-catenin and decreased the neural differentiation marker Tuj1. Similarly, genetically modified mice with forced overexpression of Vangl2 in nestin-positive cells showed decreased Tuj1 differentiation marker during embryonal development.
CONCLUSIONS: Our experimental data demonstrate that high expression of Prickle1 and Vangl2 reduce the growth of neuroblastoma cells and indicate different roles of PCP proteins in tumorigenic cells compared to normal cells. These results suggest that the activity of the non-canonical Wnt/PCP signaling pathway is important for neuroblastoma development and that manipulation of the Wnt/PCP pathway provides a possible therapy for neuroblastoma.

Wu D, Niu X, Pan H, et al.
MicroRNA-335 is downregulated in bladder cancer and inhibits cell growth, migration and invasion via targeting ROCK1.
Mol Med Rep. 2016; 13(5):4379-85 [PubMed] Related Publications
The expression of microRNA‑335 (miR‑335) has been demonstrated to be downregulated in numerous types of cancer. Thus far, no previous studies have investigated the miR‑335 expression in bladder cancer. In the present study, the expression and effects of miR‑335 were assessed in bladder cancer. The results of the present study provided, to the best of our knowledge, the first evidence that miR‑335 is downregulated in the tumor tissue of patients with bladder cancer. Following transfection of miR‑335, MTT, cell migration and invasion, luciferase and western blot assays were conducted in bladder cancer cell lines. The results demonstrated that miR‑335 inhibited cell proliferation, migration and invasion in T24 and EJ cells. In addition, the results suggested that miR‑335 directly targets Rho‑associated protein kinase 1 (ROCK1) in bladder cancer. The present study provided a novel therapeutic target, the miR‑335/ROCK1 axis in bladder cancer. The suggested approach will be beneficial in developing an effective treatment against bladder cancer.

Wang Y, Sun J, Ma C, et al.
Reduced Expression of Galectin-9 Contributes to a Poor Outcome in Colon Cancer by Inhibiting NK Cell Chemotaxis Partially through the Rho/ROCK1 Signaling Pathway.
PLoS One. 2016; 11(3):e0152599 [PubMed] Free Access to Full Article Related Publications
Galectin-9 is a widely expressed protein that is involved in immune regulation and tumorpathogenesis and serves as a marker of a poor prognosis in various types of cancers. However, the clinical impact and the precise mechanism by which this protein contributes to colon tumor progression are unclear. In the present study, we detected the expression of galectin-9 and CD56 cells using immunohistochemistry. Spearman's rank correlation was used to clarify the association between galectin-9 expression and natural killer (NK) cell infiltration. The influence of galectin-9 on NK-92 cell migration was evaluated in vitro using transwell chemotaxis assays. The role of rh-galectin-9 in F-actin polarization in NK-92 cells was investigated using laser scanning confocal microscopy. We showed that galectin-9 was expressed in 101 (78.91%) colon tumor tissues and that was expressed at lower levels in these tissues than in para-tumor tissues. Low levels of galectin-9 expression were positively correlated with a poor histological grade and lymph node metastasis (P<0.05). A Kaplan-Meier method and Cox proportional hazards regression analysis showed that overall survival was longer in patients with high galectin-9 expression in an 8-year follow-up (P<0.05). Spearman's rank correlation indicated that there was a linear correlation between galectin-9 expression and CD56+ NK cell infiltration (R(2) = 0.658; P<0.0001). Galectin-9 stimulated migration in human NK-92 cells by affecting F-actin polarization through the Rho/ROCK1 signaling pathway. These results suggest that galectin-9 expression potentially represents a novel mechanism for tumors to escape immune surveillance in colon tumors.

Hong J, Li D, Cao W
Rho Kinase ROCK2 Mediates Acid-Induced NADPH Oxidase NOX5-S Expression in Human Esophageal Adenocarcinoma Cells.
PLoS One. 2016; 11(2):e0149735 [PubMed] Free Access to Full Article Related Publications
Mechanisms of the progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA) are not fully understood. We have shown that NOX5-S may be involved in this progression. However, how acid upregulates NOX5-S is not well known. We found that acid-induced increase in NOX5-S expression was significantly decreased by the Rho kinase (ROCK) inhibitor Y27632 in BE mucosal biopsies and FLO-1 EA cells. In addition, acid treatment significantly increased the Rho kinase activity in FLO-1 cells. The acid-induced increase in NOX5-S expression and H2O2 production was significantly decreased by knockdown of Rho kinase ROCK2, but not by knockdown of ROCK1. Conversely, the overexpression of the constitutively active ROCK2, but not the constitutively active ROCK1, significantly enhanced the NOX5-S expression and H2O2 production. Moreover, the acid-induced increase in Rho kinase activity and in NOX5-S mRNA expression was blocked by the removal of calcium in both FLO-1 and OE33 cells. The calcium ionophore A23187 significantly increased the Rho kinase activity and NOX5-S mRNA expression. We conclude that acid-induced increase in NOX5-S expression and H2O2 production may depend on the activation of ROCK2, but not ROCK1, in EA cells. The acid-induced activation of Rho kinase may be mediated by the intracellular calcium increase. It is possible that persistent acid reflux present in BE patients may increase the intracellular calcium, activate ROCK2 and thereby upregulate NOX5-S. High levels of reactive oxygen species derived from NOX5-S may cause DNA damage and thereby contribute to the progression from BE to EA.

Zhao H, Jiao Y, Zhang Z
Deguelin inhibits the migration and invasion of lung cancer A549 and H460 cells via regulating actin cytoskeleton rearrangement.
Int J Clin Exp Pathol. 2015; 8(12):15582-90 [PubMed] Free Access to Full Article Related Publications
Deguelin, the main components from Mundulea sericea, was reported to suppress the growth of various cancer cells. However, the effect of Deguelin on tumor cell invasion and metastasis and its mechanism still unclear so far. In this study, we investigated the effects of Deguelin on the cell invasion in human lung cancer A549 and H460 cells. Our results demonstrate that Deguelin can significantly inhibited cell proliferation, cell migration and cell invasion. Moreover, Deguelin could also affected reorganization of the actin cytoskeleton and decreased filopodia and lamellipodia formation. Furthermore, deguelin-treated tumors showed decreased the tumor metastasis related genes such as CD44, MMP2 and MMP9 at protein and mRNA levels and the content of CEA, SCC, NSE, CYFAR21-1. In addition, Deguelin down-regulated protein expression of Rac1 and Rock1, which are impotent in actin cytoskeleton rearrangements and cell motility. Together, our results suggest that Deguelin inhibit tumor growth and metastasis of lung cancer cells and might be a candidate compound for curing lung cancer.

Song LJ, Liu Q, Meng XR, et al.
DLC-1 is an independent prognostic marker and potential therapeutic target in hepatocellular cancer.
Diagn Pathol. 2016; 11:19 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The 5-year survival rate of patients with hepatocellular cancer (HCC) was very low because of invasion and metastasis in the early stage. Biomarkers might help predict early occurrence of invasion and metastasis. Accumulating evidence has shown that deleted in liver cancer-1 (DLC1) may be considered as a metastasis suppressor gene in numerous solid and hematological cancers. However, its prognostic role and mechanisms that regulate and coordinate these activities remain poorly understood.
METHODS: With the method of immunohistochemistry, the expression of DLC-1 as well as Rho A, ROCK2, moesin had been characterized in 80 HCC tissues and adjacent noncancerous tissues. The correlation between their expression and their relationships with clinicopathological characteristics of HCC were also investigated. In addition, the prognostic value of DLC1 expression within the tumor tissues was assessed by Cox regression and Kaplan-Meier analysis.
RESULTS: DLC1 expression was significantly lower in HCC tissues than in adjacent noncancerous tissues, and DLC-1 expression was found to be negatively correlated with tumor differentiation, TNM stage and lymph node metastasis. Furthermore, DLC-1 expression was found to inversely correlate with Rho A, ROCK2 and moesin which were all highly expressed in HCC tissues. Kaplan-Meier analysis showed that significantly longer 5-year survival rate was seen in HCC patients with higher DLC1 expression, compared to those with lower expression of DLC1. Multivariate Cox proportional hazard analyses revealed that DLC1 was an independent factor affecting the overall survival probability.
CONCLUSION: DLC1 could be served as a tumor suppressor gene in the progression especially in the invasion and metastasis of HCC. DLC1 perhaps played its role by regulating the expression of Rho A, ROCK2 and moesin. Evaluation of the expression of DLC-1 might be a good prognostic marker for patients with HCC.

Gentry EG, Henderson BW, Arrant AE, et al.
Rho Kinase Inhibition as a Therapeutic for Progressive Supranuclear Palsy and Corticobasal Degeneration.
J Neurosci. 2016; 36(4):1316-23 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative four-repeat tauopathies with no cure. Mitigating pathogenic tau levels is a rational strategy for tauopathy treatment, but therapeutic targets with clinically available drugs are lacking. Here, we report that protein levels of the Rho-associated protein kinases (ROCK1 and ROCK2), p70 S6 kinase (S6K), and mammalian target of rapamycin (mTOR) were increased in PSP and CBD brains. RNAi depletion of ROCK1 or ROCK2 reduced tau mRNA and protein level in human neuroblastoma cells. However, additional phenotypes were observed under ROCK2 knockdown, including decreased S6K and phosphorylated mTOR levels. Pharmacologic inhibition of Rho kinases in neurons diminished detergent-soluble and -insoluble tau through a combination of autophagy enhancement and tau mRNA reduction. Fasudil, a clinically approved ROCK inhibitor, suppressed rough eye phenotype and mitigated pathogenic tau levels by inducing autophagic pathways in a Drosophila model of tauopathy. Collectively, these findings highlight the Rho kinases as rational therapeutic targets to combat tau accumulation in PSP and CBD.
SIGNIFICANCE STATEMENT: Studies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) suggest that mitigating pathogenic tau levels is a rational strategy for tauopathy treatment. In this report, the Rho-associated protein kinases (ROCK1 and ROCK2) are identified as novel drug targets for PSP and CBD. We show that elevated insoluble tau levels are associated with increased ROCK1 and ROCK2 in PSP and CBD brains, whereas experiments in cellular and animal models identify pharmacologic inhibition of ROCKs as a mechanism-based approach to reduce tau levels. Our study correlates bona fide changes in PSP and CBD brains with cellular models, identifies drug targets, and tests the therapeutic in vivo.

Lim B, Kim C, Kim JH, et al.
Genetic alterations and their clinical implications in gastric cancer peritoneal carcinomatosis revealed by whole-exome sequencing of malignant ascites.
Oncotarget. 2016; 7(7):8055-66 [PubMed] Free Access to Full Article Related Publications
Peritoneal carcinomatosis accompanied by malignant ascites is a major cause of death of advanced gastric cancer (GC). To comprehensively characterize the underlying genomic events involved in GC peritoneal carcinomatosis, we analyzed whole-exome sequences of normal gastric tissues, primary tumors, and malignant ascites from eight GC patients. We identified a unique mutational signature biased toward C-to-A substitutions in malignant ascites. In contrast, the patients who received treatment of adjuvant chemotherapy showed a high rate of C-to-T substitutions along with hypermutation in malignant ascites. Comparative analysis revealed several candidate mutations for GC peritoneal carcinomatosis: recurrent mutations in COL4A6, INTS2, and PTPN13; mutations in druggable genes including TEP1, PRKCD, BRAF, ERBB4, PIK3CA, HDAC9, FYN, FASN, BIRC2, FLT3, ROCK1, CD22, and PIK3C2B; and mutations in metastasis-associated genes including TNFSF12, L1CAM, DIAPH3, ROCK1, TGFBR1, MYO9B, NR4A1, and RHOA. Notably, gene ontology analysis revealed the significant enrichment of mutations in the Rho-ROCK signaling pathway-associated biological processes in malignant ascites. At least four of the eight patients acquired somatic mutations in the Rho-ROCK pathway components, suggesting the possible relevance of this pathway to GC peritoneal carcinomatosis. These results provide a genome-wide molecular understanding of GC peritoneal carcinomatosis and its clinical implications, thereby facilitating the development of effective therapeutics.

Mohammadi-Yeganeh S, Paryan M, Arefian E, et al.
MicroRNA-340 inhibits the migration, invasion, and metastasis of breast cancer cells by targeting Wnt pathway.
Tumour Biol. 2016; 37(7):8993-9000 [PubMed] Related Publications
MicroRNAs (miRNAs) play a key role in tumor metastasis based on their capacity to regulate the expression of tumor-related genes. Over-expression of key genes such as c-MYC and CTNNB1 (encoding β-catenin) in Wnt/β-catenin-dependent and ROCK1 in Wnt/β-catenin-independent signaling pathways (Rho/Rho-associated kinase (ROCK) signaling pathway) has already been identified as the hallmarks of many tumors, and their role in breast cancer has also been investigated and confirmed. miR-340 characterization as an onco-suppressor miRNA has been previously reported. However, the mechanism by which it inhibits metastasis has not been completely elucidated. Quantitative real-time PCR (qPCR), Western blot, and luciferase assays were used to confirm the effect of miR-340 on the 3'-untranslated region (UTR) of the target genes. Lentiviral particles containing miR-340 were also used to evaluate the effect of miR-340 restoration on cell proliferation, migration, and invasion in vitro in the invasive MDA-MB-231 cell line. By applying bioinformatic approaches for the prediction of miRNAs targeting 3'-UTRs of CTNNB1, c-MYC, and ROCK1, we found out that miR-340 could dramatically down-regulate metastasis by targeting Wnt signaling in breast cancer cells. In the current study, analyzing miR-340 by reverse transcription quantitative PCR (RT-qPCR) in MDA-MB-231 showed that it was remarkably down-regulated in the metastatic breast cancer cell line. We found that restoration of miR-340 in the invasive breast cancer cell line, MDA-MB-231, suppresses the expression of the target genes' messenger RNA (mRNA) and protein and, as a result, inhibits tumor cell invasion and metastasis. Our findings highlight the ability of bioinformatic approaches to find miRNAs targeting specific genes. By bioinformatic analysis, we confirmed the important role of miR-340 as a pivotal regulator of breast cancer metastasis in targeting previously validated (ROCK1) and potentially novel genes, i.e., (CTNNB1 and c-MYC).

Xue H, Guo X, Han X, et al.
MicroRNA-584-3p, a novel tumor suppressor and prognostic marker, reduces the migration and invasion of human glioma cells by targeting hypoxia-induced ROCK1.
Oncotarget. 2016; 7(4):4785-805 [PubMed] Free Access to Full Article Related Publications
Here, we report that microRNA-584-3p (miR-584-3p) is up-regulated in hypoxic glioma cells and in high-grade human glioma tumors (WHO grades III-IV) relative to normoxic cells and to low-grade tumors (WHO grades I-II), respectively. The postoperative survival time was significantly prolonged in the high-grade glioma patients with high miR-584-3p expression compared with those with low miR-584-3p expression. miR-584-3p may function as a potent tumor suppressor and as a prognostic biomarker for malignant glioma. However, the molecular mechanisms underlying these properties remain poorly understood. Our mechanistic studies revealed that miR-584-3p suppressed the migration and invasion of glioma cells by disrupting hypoxia-induced stress fiber formation. Specifically, we have found that ROCK1 is a direct and functionally relevant target of miR-584-3p in glioma cells. Our results have demonstrated a tumor suppressive function of miR-584-3p in glioma, in which it inhibits the migration and invasion of tumor cells by antagonizing hypoxia-induced, ROCK1-dependent stress fiber formation. Our findings have potential implications for glioma gene therapy and suggest that miR-584-3p could represent a prognostic indicator for glioma.

Zheng M, Sun X, Li Y, Zuo W
MicroRNA-145 inhibits growth and migration of breast cancer cells through targeting oncoprotein ROCK1.
Tumour Biol. 2016; 37(6):8189-96 [PubMed] Related Publications
MicroRNAs are small non-coding RNAs that may also function as oncogenes and tumor suppressor genes, as the abnormal expression of microRNAs is associated with various human tumors. MicroRNA-145 (miR-145) inhibits growth and increases chemo- or radiosensitivity in various cancers. However, the role of miR-145 in breast cancer progression remains unknown. In this study, miR-145 expression level was measured via quantitative real-time PCR in 88 pairs of human breast cancer tissues and adjacent normal tissues and in a panel of human breast cancer cell lines. Cell proliferation and cell migration were assessed by cell viability assay and transwell assay. Western blot was used to verify Rho-associated protein kinase 1 (ROCK1) as a novel target gene of miR-145. Our results showed that miR-145 was frequently downregulated in breast cancer tissues and cell lines. Overexpression of miR-145 in MCF-7 and BT-549 cell lines significantly inhibited cell proliferation, migration, and invasion in vitro. ROCK1 was identified as a target of miR-145, and ectopic expression of miR-145 downregulated ROCK1. Our findings indicate that miR-145 acts as a tumor suppressor and its downregulation in tumor tissues may contribute to the progression of breast cancer through a mechanism involving ROCK1, suggesting miR-145 as a potential new diagnostic and therapeutic target for the treatment of breast cancer.

Rivera IG, Ordoñez M, Presa N, et al.
Ceramide 1-phosphate regulates cell migration and invasion of human pancreatic cancer cells.
Biochem Pharmacol. 2016; 102:107-19 [PubMed] Related Publications
Pancreatic cancer is an aggressive and devastating disease characterized by invasiveness, rapid progression and profound resistance to treatment. Despite years of intense investigation, the prognosis of this type of cancer is poor and there is no efficacious treatment to overcome the disease. Using human PANC-1 and MIA PaCa-2 cells, we demonstrate that the bioactive sphingolipid ceramide 1-phosphate (C1P) increases pancreatic cancer cell migration and invasion. Treatment of these cells with selective inhibitors of phosphatidylinositol 3-kinase (PI3K), Akt1, or mammalian target of rapamycin 1 (mTOR1), or with specific siRNAs to silence the genes encoding these kinases, resulted in potent inhibition of C1P-induced cell migration and invasion. Likewise, the extracellularly regulated kinases 1 and 2 (ERK1-2), and the small GTPase RhoA, which regulates cytoskeleton reorganization, were also found to be implicated in C1P-stimulated ROCK1-dependent cancer cell migration and invasion. In addition, pre-treatment of the cancer cells with pertussis toxin abrogated C1P-induced cell migration, suggesting the intervention of a Gi protein-coupled receptor in this process. Pancreatic cancer cells engineered to overexpress ceramide kinase (CerK), the enzyme responsible for C1P biosynthesis in mammalian cells, showed enhanced spontaneous cell migration that was potently blocked by treatment with the selective CerK inhibitor NVP-231, or by treatment with specific CerK siRNA. Moreover, overexpression of CerK with concomitant elevations in C1P enhanced migration of pancreatic cancer cells. Collectively, these data demonstrate that C1P is a key regulator of pancreatic cancer cell motility, and suggest that targeting CerK expression/activity and C1P may be relevant factors for controlling pancreatic cancer cell dissemination.

Hsu CY, Chang ZF, Lee HH
Immunohistochemical evaluation of ROCK activation in invasive breast cancer.
BMC Cancer. 2015; 15:943 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Two isoforms of Rho-associated coiled-coil kinase (ROCK), ROCKI and ROCKII, play an important role in many cellular processes. Despite the accumulating evidence showing that ROCK could be a potential cancer therapeutic target, the relevant tumor types to ROCK activation are not well clarified. The aim of this study was to evaluate the ROCK activation status in different tumor types of breast cancer.
RESULTS: We evaluated the immunoreactivities of phosphorylation-specific antibodies of ROCKI and ROCKII to inform their kinase activation in 275 of breast carcinoma tissues, including 56 of carcinoma in situ, 116 of invasive carcinoma, and 103 of invasive carcinoma with metastasis. ROCKII activation signal detected in nucleus was significantly correlated with tumor metastasis, while ROCKI and cytosolic ROCKII activation signals made no significant difference in that metastasis. Furthermore, nuclear ROCKII activation signal was associated with poor clinical outcome and correlated with late tumor stage, low expression of estrogen receptor (ER) and progesterone receptor (PR), overexpression of human epidermal growth factor receptor 2 (HER2) and high Ki67 labeling index.
CONCLUSIONS: Nuclear ROCKII activation signal might contribute to the tumor metastasis in breast cancer. Differences in ROCK activation that underlie the phenotypes of breast cancer could enhance our understanding for the use of ROCK inhibitors in cancer therapy.

Ding W, Tan H, Zhao C, et al.
MiR-145 suppresses cell proliferation and motility by inhibiting ROCK1 in hepatocellular carcinoma.
Tumour Biol. 2016; 37(5):6255-60 [PubMed] Related Publications
MicroRNAs (miRNAs) play key roles in cancer development and progression. In the present study, we investigated the role of miR-145 in the progression of hepatocellular carcinoma (HCC). Ten HCC cell lines and samples from 96 patients with HCC were analyzed for the expression of miR-145 by quantitative real-time polymerase chain reaction (qRT-PCR). Overexpression of miR-145 was established by transfecting mimics into HepG2 and QGY-7703 cells. Cell proliferation and cell migration were assessed by cell viability assay and transwell assay. Western blot was to verify ROCK1 as a novel target gene of miR-145. Our results showed that miR-145 was frequently downregulated in HCC tumors and cell lines. Overexpression of miR-145 in HCC cell lines significantly inhibited cell proliferation, migration, and invasion in vitro. ROCK1 was identified as a target of miR-145, and ectopic expression of miR-145 downregulated ROCK1. Together, these findings indicate that miR-145 acts as a tumor suppressor and its downregulation in tumor tissues may contribute to the progression and metastasis of HCC through a mechanism involving ROCK1, suggesting miR-145 as a potential new diagnostic and therapeutic target for the treatment of HCC.

Zucchini C, Martinelli M, De Sanctis P, et al.
Possible Gender-Related Modulation by the ROCK1 Gene in Colorectal Cancer Susceptibility.
Pathobiology. 2015; 82(6):252-8 [PubMed] Related Publications
AIM: In view of accumulating evidence supporting a pivotal role of the Rho/ROCK pathway in cancer, we investigated Rho-kinase polymorphisms as potential susceptibility factors in colorectal cancer (CRC) in a representative sample of the Italian population.
METHODS: DNA obtained from the peripheral blood samples of 137 CRC patients and 141 healthy controls was genotyped for four ROCK1 (rs35996865; rs73963110; rs2127958; rs288980) and five ROCK2 (rs12692437; rs7563468; rs35768389; rs17463896; rs16857265) selected single nucleotide polymorphisms.
RESULTS: None of the allelic variants of the nine selected markers was associated with the occurrence of CRC or with the development of regional lymph node metastasis. By contrast, the ROCK1 rs35996865 G variant allele was significantly more frequent in male patients (p = 0.028) than in the control group.
CONCLUSION: This finding is, at present, the first that points to a possible gender-related modulation by the ROCK1 gene in CRC susceptibility.

Ching RH, Lau EY, Ling PM, et al.
Phosphorylation of nucleophosmin at threonine 234/237 is associated with HCC metastasis.
Oncotarget. 2015; 6(41):43483-95 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is frequently complicated by the occurrence of intrahepatic and extrahepatic metastases, leading to poor prognosis. To improve the prognosis for HCC patients, there is an urgent need to understand the molecular mechanisms of metastasis in HCC. Since protein Serine/Threonine phosphorylation emerges to be an important posttranslational modification critical in signaling process associated with cell proliferation, survival and metastasis, we employed a pair of primary tumor-derived and corresponding lung-metastatic counterparts (PLC/PRF/5-PT and PLC/PRF/5-LM) and aimed to identify these changes using CelluSpot Serine/Threonine kinase peptide array. Upon analysis, we found phosphorylated level of nucleophosmin (NPM) at Threonine 234/237 (p-NPM-Thr234/237) had remarkably high level in metastatic HCC cells (PLC-LM) than the corresponding primary HCC cell line (PLC-PT). Similar observation was observed in another match primary and their metastatic counterparts (MHCC-97L and MHCC-97H). By immunohistochemical staining, p-NPM-Thr234/237 was consistently found to be preferentially expressed in metastatic HCCs when compared with primary HCC in 28 HCC cases (p < 0.0001). By overexpressing Flag-tagged NPM and its phosphorylation site mutant (Thr234/237A) into low p-NPM-Thr234/237 expressing cells (Hep3B and Huh7) using a lentiviral based approach, we demonstrated that p-NPM-Thr234/237 is critical in invasion and migration of HCC cells, and this effect was mediated by cyclin-dependent kinase 1 (CDK1). Wild-type NPM was found to physically interact with a metastatic gene, ROCK2, and defective in Thr234/237 phosphorylation decreased its binding affinity, resulting in decrease in ROCK2 mediated signaling pathway. Identification of CDK1/p-NPM/ROCK2 signaling pathway provides a novel target for molecular therapy against HCC metastasis.

Niu Z, Wang M, Zhou L, et al.
Elevated GRP78 expression is associated with poor prognosis in patients with pancreatic cancer.
Sci Rep. 2015; 5:16067 [PubMed] Free Access to Full Article Related Publications
Glucose-regulated protein 78 (GRP78) is a member of the heat-shock protein 70 family. We evaluated the expression of GRP78 using tissue microarray-based immunohistochemistry in tumor tissues and adjacent nontumor tissues from 180 pancreatic ductal adenocarcinoma (PDAC) patients. The associations between the expression levels of GRP78, clinicopathological factors, and overall survival were evaluated. The results showed that the expression of GRP78 was significantly higher in PDAC cells than in normal pancreatic duct cells within adjacent nontumor tissues (p < 0.05). The increased expression of GRP78 in the tumor tissues was significantly correlated with a higher T-stage (p < 0.05) and a shorter overall survival (OS, p < 0.05). In an in vitro study, the regulation of GRP78 in the PDAC cell lines affected the proliferation, migration, and invasion of PDAC cells through the regulation of CyclinD1, cyclin-dependent kinase (CDK) 4, CDK6, phospho-signal transducer, activator of transcription 3 (p-STAT3), janus kinase 2 (JAK2), ras homolog gene family member A (RhoA), Rho-associated kinase 1 (ROCK1), and sterile alpha motif domain containing protein 4 (Smad4). The present data suggest that GRP78 plays a crucial role in the proliferation, migration, and invasion of pancreatic cancer cells and may be a suitable prognostic marker in PDAC.

Chin VT, Nagrial AM, Chou A, et al.
Rho-associated kinase signalling and the cancer microenvironment: novel biological implications and therapeutic opportunities.
Expert Rev Mol Med. 2015; 17:e17 [PubMed] Free Access to Full Article Related Publications
The Rho/ROCK pathway is involved in numerous pivotal cellular processes that have made it an area of intense study in cancer medicine, however, Rho-associated coiled-coil containing protein kinase (ROCK) inhibitors are yet to make an appearance in the clinical cancer setting. Their performance as an anti-cancer therapy has been varied in pre-clinical studies, however, they have been shown to be effective vasodilators in the treatment of hypertension and post-ischaemic stroke vasospasm. This review addresses the various roles the Rho/ROCK pathway plays in angiogenesis, tumour vascular tone and reciprocal feedback from the tumour microenvironment and explores the potential utility of ROCK inhibitors as effective vascular normalising agents. ROCK inhibitors may potentially enhance the delivery and efficacy of chemotherapy agents and improve the effectiveness of radiotherapy. As such, repurposing of these agents as adjuncts to standard treatments may significantly improve outcomes for patients with cancer. A deeper understanding of the controlled and dynamic regulation of the key components of the Rho pathway may lead to effective use of the Rho/ROCK inhibitors in the clinical management of cancer.

Fujimura K, Choi S, Wyse M, et al.
Eukaryotic Translation Initiation Factor 5A (EIF5A) Regulates Pancreatic Cancer Metastasis by Modulating RhoA and Rho-associated Kinase (ROCK) Protein Expression Levels.
J Biol Chem. 2015; 290(50):29907-19 [PubMed] Free Access to Full Article Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with an overall survival rate of less than 5%. The poor patient outcome in PDAC is largely due to the high prevalence of systemic metastasis at the time of diagnosis and lack of effective therapeutics that target disseminated cells. The fact that the underlying mechanisms driving PDAC cell migration and dissemination are poorly understood have hindered drug development and compounded the lack of clinical success in this disease. Recent evidence indicates that mutational activation of K-Ras up-regulates eIF5A, a component of the cellular translational machinery that is critical for PDAC progression. However, the role of eIF5A in PDAC cell migration and metastasis has not been investigated. We report here that pharmacological inhibition or genetic knockdown of eIF5A reduces PDAC cell migration, invasion, and metastasis in vitro and in vivo. Proteomic profiling and bioinformatic analyses revealed that eIF5A controls an integrated network of cytoskeleton-regulatory proteins involved in cell migration. Functional interrogation of this network uncovered a critical RhoA/ROCK signaling node that operates downstream of eIF5A in invasive PDAC cells. Importantly, eIF5A mediates PDAC cell migration and invasion by modulating RhoA/ROCK protein expression levels. Together our findings implicate eIF5A as a cytoskeletal rheostat controlling RhoA/ROCK protein expression during PDAC cell migration and metastasis. Our findings also implicate the eIF5A/RhoA/ROCK module as a potential new therapeutic target to treat metastatic PDAC cells.

Deng Q, Xie L, Li H
MiR-506 suppresses cell proliferation and tumor growth by targeting Rho-associated protein kinase 1 in hepatocellular carcinoma.
Biochem Biophys Res Commun. 2015; 467(4):921-7 [PubMed] Related Publications
Recent studies have shown that miR-506 plays important roles in human cancer progression. However, little is known about the function of miR-506 in hepatocellular carcinoma (HCC). In this study, we found that miR-506 significantly inhibits HCC cell proliferation in vitro and tumorigenicity in vivo. Moreover, miR-506 induced G1/S cell cycle arrest and apoptosis in HCC cells. Rho-associated protein kinase 1(ROCK1) was identified as a novel target of miR-506; overexpression of ROCK1 reversed the suppressive effects of miR-506 in HCC cells. Additionally, ROCK1 was found up-regulated and inversely correlated with miR-506 in HCC tissues. Therefore, our findings collectively suggest that miR-506 acts as a tumor suppressor via regulation of ROCK1 expression and may thus be a promising therapeutic target for HCC.

Herraiz C, Calvo F, Pandya P, et al.
Reactivation of p53 by a Cytoskeletal Sensor to Control the Balance Between DNA Damage and Tumor Dissemination.
J Natl Cancer Inst. 2016; 108(1) [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Abnormal cell migration and invasion underlie metastasis, and actomyosin contractility is a key regulator of tumor invasion. The links between cancer migratory behavior and DNA damage are poorly understood.
METHODS: Using 3D collagen systems to recapitulate melanoma extracellular matrix, we analyzed the relationship between the actomyosin cytoskeleton of migrating cells and DNA damage. We used multiple melanoma cell lines and microarray analysis to study changes in gene expression and in vivo intravital imaging (n = 7 mice per condition) to understand how DNA damage impacts invasive behavior. We used Protein Tissue Microarrays (n = 164 melanomas) and patient databases (n = 354 melanoma samples) to investigate the associations between markers of DNA damage and actomyosin cytoskeletal features. Data were analyzed with Student's and multiple t tests, Mann-Whitney's test, one-way analysis of variance, and Pearson correlation. All statistical tests were two-sided.
RESULTS: Melanoma cells with low levels of Rho-ROCK-driven actomyosin are subjected to oxidative stress-dependent DNA damage and ATM-mediated p53 protein stabilization. This results in a specific transcriptional signature enriched in DNA damage/oxidative stress responsive genes, including Tumor Protein p53 Inducible Protein 3 (TP53I3 or PIG3). PIG3, which functions in DNA damage repair, uses an unexpected catalytic mechanism to suppress Rho-ROCK activity and impair tumor invasion in vivo. This regulation was suppressed by antioxidants. Furthermore, PIG3 levels decreased while ROCK1/2 levels increased in human metastatic melanomas (ROCK1 vs PIG3; r = -0.2261, P < .0001; ROCK2 vs PIG3: r = -0.1381, P = .0093).
CONCLUSIONS: The results suggest using Rho-kinase inhibitors to reactivate the p53-PIG3 axis as a novel therapeutic strategy; we suggest that the use of antioxidants in melanoma should be very carefully evaluated.

Cai SD, Chen JS, Xi ZW, et al.
MicroRNA‑144 inhibits migration and proliferation in rectal cancer by downregulating ROCK‑1.
Mol Med Rep. 2015; 12(5):7396-402 [PubMed] Free Access to Full Article Related Publications
Cancer of the colon and rectum are two distinct entities, which require different treatment strategies and separate treatment. MicroRNAs (miRNAs) act as critical regulators of genes involved in several biological processes. Aberrant alterations of miRNAs have been found in several types of cancer, including colon cancer and rectal cancer. Extensive catalogues of downregulated miRNAs have been identified for colon cancer, whereas only limited data are available for rectal cancer. An example of miRNA profiling in a previous study found that miRNA (miR)‑144 showed aberrant expression and appeared to be rectal cancer‑specific, its expression not being reported in colon cancer. In the present study, the role of miR‑144 in rectal cancer was investigated. SW837 and SW1463 cell lines were selected as rectal cell carcinoma cells. Using reverse transcription-quantitative polymerase chain reaction, western blot, BrdU, cell migration and cell viability assays, it was found that the expression levels of miR‑144 were significantly reduced in the SW837 and SW1463 cell lines, and the overexpression of miR‑144 suppressed rectal cancer cell viability, migration and proliferation. In addition, Rho‑associated coiled‑coil containing protein kinase 1 (ROCK1) was identified as a target of miR‑144 in the rectal cancer cells. The supplementation of ROCK1 markedly restored the cell migration and proliferation, which was inhibited by miR‑144. Together, the data of the present study demonstrated that miR‑144 acts as a tumor suppressor by targeting ROCK1, and indicates the potential of miR‑144 as a novel biomarker and target in the treatment of rectal cancer.

Wu SH, Hsiao YT, Kuo CL, et al.
Bufalin Inhibits NCI-H460 Human Lung Cancer Cell Metastasis In Vitro by Inhibiting MAPKs, MMPs, and NF-κB Pathways.
Am J Chin Med. 2015; 43(6):1247-64 [PubMed] Related Publications
Bufalin, a component of Chan Su (a traditional Chinese medicine), has been known to have antitumor effects for thousands of years. In this study, we investigated its anti-metastasis effects on NCI-H460 lung cancer cells. Under sub-lethal concentrations (from 25 up to 100 nM), bufalin significantly inhibits the invasion and migration nature of NCI-H460 cells that were measured by Matrigel Cell Migration Assay and Invasion System. Bufalin also suppressed the enzymatic activity of matrix metalloproteinase (MMP)-9, which was examined by gelatin zymography methods. Western blotting revealed that bufalin depressed several key metastasis-related proteins, such as NF-κB, MMP-2, MMP-9, protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3-K), phosphorylated Akt, growth factor receptor-bound protein 2 (GRB2), phosphorylated extracellular signal-regulated kinase (ERK), phosphorylated p38, and phosphorylated c-Jun NH2-terminal kinase (JNK). As evidenced by immunostaining and the electrophoretic mobility shift assay (EMSA), bufalin induced not only a decreased cytoplasmic NF-κB production, but also decreased its nuclear translocation. Several metastasis-related genes, including Rho-associated (Rho A), coiled-coil-containing protein kinase 1 (ROCK1), and focal adhesion kinase (FAK), were down-regulated after bufalin treatment. In conclusion, bufalin is effective in inhibiting the metastatic nature of NCI-H460 cells in low, sub-lethal concentrations. Such an effect involves many mechanisms including MMPs, mitogen-activated protein kinases (MAPKs) and NF-κB systems. Bufalin has a potential to evolve into an anti-metastasis drug for human lung cancer in the future.

Leve F, Peres-Moreira RJ, Binato R, et al.
LPA Induces Colon Cancer Cell Proliferation through a Cooperation between the ROCK and STAT-3 Pathways.
PLoS One. 2015; 10(9):e0139094 [PubMed] Free Access to Full Article Related Publications
Lysophosphatidic acid (LPA) plays a critical role in the proliferation and migration of colon cancer cells; however, the downstream signaling events underlying these processes remain poorly characterized. The aim of this study was to investigate the signaling pathways triggered by LPA to regulate the mechanisms involved in the progression of colorectal cancer (CRC). We have used three cell line models of CRC, and initially analyzed the expression profile of LPA receptors (LPAR). Then, we treated the cells with LPA and events related to their tumorigenic potential, such as migration, invasion, anchorage-independent growth, proliferation as well as apoptosis and cell cycle were evaluated. We used the Chip array technique to analyze the global gene expression profiling that occurs after LPA treatment, and we identified cell signaling pathways related to the cell cycle. The inhibition of these pathways verified the conclusions of the transcriptomic analysis. We found that the cell lines expressed LPAR1, -2 and -3 in a differential manner and that 10 μM LPA did not affect cell migration, invasion and anchorage-independent growth, but it did induce proliferation and cell cycle progression in HCT-116 cells. Although LPA in this concentration did not induce transcriptional activity of β-catenin, it promoted the activation of Rho and STAT-3. Moreover, ROCK and STAT-3 inhibitors prevented LPA-induced proliferation, but ROCK inhibition did not prevent STAT-3 activation. Finally, we observed that LPA regulates the expression of genes related to the cell cycle and that the combined inhibition of ROCK and STAT-3 prevented cell cycle progression and increased the LPA-induced expression of cyclins E1, A2 and B1 to a greater degree than either inhibitor alone. Overall, these results demonstrate that LPA increases the proliferative potential of colon adenocarcinoma HCT-116 cells through a mechanism involving cooperation between the Rho-ROCK and STAT3 pathways involved in cell cycle control.

Xiang J, Wu Y, Li DS, et al.
miR-584 Suppresses Invasion and Cell Migration of Thyroid Carcinoma by Regulating the Target Oncogene ROCK1.
Oncol Res Treat. 2015; 38(9):436-40 [PubMed] Related Publications
BACKGROUND: Uncovering the target gene of miR-584 to control thyroid carcinoma (TC) invasion and migration is of central importance in the diagnosis, treatment, and prognosis of TC. To validate whether miR-584 has a tumor-suppressive role in thyroid cancer cells by targeting ROCK1, a series of experiments were conducted to figure out the mechanism of action of miR-584.
MATERIAL AND METHODS: Migration analyses and cell proliferation assays were performed using miR-584-transfected cells. The expression levels of miR-584 in TC were detected by using real-time polymerase chain reaction (PCR). Western blot analyses were conducted to find out the relationship between the tumor suppressor miR-584 and the target oncogene ROCK1 protein expression levels. Wound healing experiments were used to examine the relationships between miR-584 and the migration of thyroid cancer K1 cells and the effects of ROCK1 knockdown on K1 cell motility.
RESULTS: Our results demonstrate that altering the miR-584 levels affects human thyroid cancer cell migration, but has no effect on cell proliferation. The relative ROCK-1 expression levels were 1 and 0.54 in the scrambled-sequence control group and the miR-584 group, respectively. K1 cells transfected with siRNA-ROCK-1 showed weaker cell migration than cells transfected with siRNA-NC (negative control); the cell motility ratios were 18% and 27%, respectively.
CONCLUSION: These results indicate that miR-584 could inhibit the expression of ROCK1, and ROCK1 knockdown would further affect the migration ability of K1 cells.

Xu B, Huang Y, Niu X, et al.
Hsa-miR-146a-5p modulates androgen-independent prostate cancer cells apoptosis by targeting ROCK1.
Prostate. 2015; 75(16):1896-903 [PubMed] Related Publications
BACKGROUND: MicroRNAs (miRNAs) have been demonstrated playing important roles in the procession of prostate cancer cells transformation from androgen-dependence to androgen-independence.
METHODS: We conducted the miRNA microarray and realtime PCR analyses in both androgen-dependent (ADPC) and androgen-independent prostate cancer (AIPC) tissues. We also explored the role of hsa-miR-146a-5p (miR-146a) in MSKCC prostate cancer clinical database. Moreover, the impact of miR-146a on prostate cancer cells apoptosis were detected by Hoechst staining and fluorescence-activated cell sorter (FACS). Its target is predicted by DIANA LAB online database and the result was assumed by western blotting and luciferase assay.
RESULTS: We demonstrated that miR-146a was down-regulated in AIPC tissues and cell lines compared to that in the ADPC tissues. In MSKCC data re-analyses, we found that miR-146a was underexpressed in metastatic prostate cancer tissues and those with Gleason score >8, moreover, low level of miR-146a represented a high biochemical relapse rate after radical prostatectomy. In the functional analyses, we transfected miR-146a mimics into CPRC cell lines and found miR-146a induced cells apoptosis. In mechanic analyses, we found that miR-146a inhibited the basal level of Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) expression by targeting its 3'UTR and an inverse correlation of expression between miR-146a and ROCK1 was observed. Moreover, caspase 3 activity was stimulated by miR-146a overexpression.
CONCLUSION: miR-146a has a critical role in the process of AIPC prostate cancer cells apoptosis through regulation of ROCK/Caspase 3 pathway. Targeting this pathway may be a promising therapeutic strategy for future personalized anti-cancer treatment.

Borin TF, Arbab AS, Gelaleti GB, et al.
Melatonin decreases breast cancer metastasis by modulating Rho-associated kinase protein-1 expression.
J Pineal Res. 2016; 60(1):3-15 [PubMed] Free Access to Full Article Related Publications
The occurrence of metastasis, an important breast cancer prognostic factor, depends on cell migration/invasion mechanisms, which can be controlled by regulatory and effector molecules such as Rho-associated kinase protein (ROCK-1). Increased expression of this protein promotes tumor growth and metastasis, which can be restricted by ROCK-1 inhibitors. Melatonin has shown oncostatic, antimetastatic, and anti-angiogenic effects and can modulate ROCK-1 expression. Metastatic and nonmetastatic breast cancer cell lines were treated with melatonin as well as with specific ROCK-1 inhibitor (Y27632). Cell viability, cell migration/invasion, and ROCK-1 gene expression and protein expression were determined in vitro. In vivo lung metastasis study was performed using female athymic nude mice treated with either melatonin or Y27832 for 2 and 5 wk. The metastases were evaluated by X-ray computed tomography and single photon emission computed tomography (SPECT) and by immunohistochemistry for ROCK-1 and cytokeratin proteins. Melatonin and Y27632 treatments reduced cell viability and invasion/migration of both cell lines and decreased ROCK-1 gene expression in metastatic cells and protein expression in nonmetastatic cell line. The numbers of 'hot' spots (lung metastasis) identified by SPECT images were significantly lower in treated groups. ROCK-1 protein expression also was decreased in metastatic foci of treated groups. Melatonin has shown to be effective in controlling metastatic breast cancer in vitro and in vivo, not only via inhibition of the proliferation of tumor cells but also through direct antagonism of metastatic mechanism of cells rendered by ROCK-1 inhibition. When Y27632 was used, the effects were similar to those found with melatonin treatment.

Tsai WC, Chen CL, Chen HC
Protein tyrosine phosphatase SHP2 promotes invadopodia formation through suppression of Rho signaling.
Oncotarget. 2015; 6(27):23845-56 [PubMed] Free Access to Full Article Related Publications
Invadopodia are actin-enriched membrane protrusions that are important for extracellular matrix degradation and invasive cell motility. Src homolog domain-containing phosphatase 2 (SHP2), a non-receptor protein tyrosine phosphatase, has been shown to play an important role in promoting cancer metastasis, but the underlying mechanism is unclear. In this study, we found that depletion of SHP2 by short-hairpin RNA suppressed invadopodia formation in several cancer cell lines, particularly in the SAS head and neck squamous cell line. In contrast, overexpression of SHP2 promoted invadopodia formation in the CAL27 head and neck squamous cell line, which expresses low levels of endogenous SHP2. The depletion of SHP2 in SAS cells significantly decreased their invasive motility. The suppression of invadopodia formation by SHP2 depletion was restored by the Clostridium botulinum C3 exoenzyme (a Rho GTPase inhibitor) or Y27632 (a specific inhibitor for Rho-associated kinase). Together, our results suggest that SHP2 may promote invadopodia formation through inhibition of Rho signaling in cancer cells.

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