CSRP2 suppresses colorectal cancer progression <i>via</i> p130Cas/Rac1 axis-meditated ERK, PAK, and HIPPO signaling pathways

Chen, Lixia; Long, Xiaoli; Duan, Shiyu; Liu, Xunhua; Chen, Jianxiong; Lan, Jiong-Cai; Liu, Xuming; Huang, Wenyan; Geng, Jiao; Zhou, Jun

doi:10.7150/thno.45674

Cited by 27 publications

(34 citation statements)

References 55 publications

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“…Specifically, RAC1-mediated cell migration is initiated by BCAR1 37 . Furthermore, the BCAR1/Rac1 axis can suppress colorectal cancer and metastasis through the Hippo, ERK, and PAK signaling pathways 38 , indicating the signaling pathway is indispensable in cell signal transduction. In addition, RAC1 regulates EMT 39 , potentially via STAT343 40 , ERK2 41 and the nuclear translocation of β-catenin 42 .…”

Section: Discussionmentioning

confidence: 99%

BCAR1 plays critical roles in the formation and immunoevasion of invasive circulating tumor cells in lung adenocarcinoma

Mao¹,

Jiang²,

Wang³

et al. 2021

Int. J. Biol. Sci.

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Background:We investigated the roles of breast cancer anti-estrogen resistance 1 (BCAR1/p130Cas) in the formation and immunoevasion of invasive circulating tumor cells (CTCs) in lung adenocarcinoma (LUAD). Methods: Biomarkers of CTCs including BCAR1 and CD274, were evaluated by the CanPatrol method. Proteomics analysis of LUAD cells and exosomes after BCAR1 overexpression (BCAR1-OE) was performed by mass spectrometry. Cell functions and relevant signaling pathways were investigated after BCAR1 knockdown (BCAR1-KO) or BCAR1-OE in LUAD cells. Lastly, in vitro and in vivo experiments were performed to confirm the roles of BCAR1 in the formation and immunoevasion of CTCs. Results: High expression of BCAR1 by CTCs correlated with CD274 expression and epithelial-tomesenchymal transition (EMT). RAC1, together with BCAR1, was found to play an important role in the carcinogenesis of LUAD. RAC1 functioned with BCAR1 to induce EMT and to enhance cell proliferation, colony formation, cell invasion and migration, and anoikis resistance in LUAD cells. BCAR1 up-regulated CD274 expression probably by shuttling the short isoform of BRD4 (BRD4-S) into the nucleus. CTCs, as well as tumor formation, were prohibited in nude mice xenografted with BCAR1-KO cells. The co-expression of BCAR1/RAC1 and BCAR1/CD274 was confirmed in LUAD. BCAR1 expression in LUAD is an indicator of poor prognosis, and it associates with immunoevasion. Conclusion: BCAR1, as a new target for the treatment of LUAD, plays roles in the formation and immunoevasion of invasive CTCs. The mechanism includes triggering EMT via RAC1 signaling and up-regulating CD274 expression by shuttling BRD4-S into the nucleus.

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Section: Discussionmentioning

confidence: 99%

BCAR1 plays critical roles in the formation and immunoevasion of invasive circulating tumor cells in lung adenocarcinoma

Mao¹,

Jiang²,

Wang³

et al. 2021

Int. J. Biol. Sci.

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“…The same research group could show in a study focusing on paxillin and protein tyrosine phosphatase receptor T (PTPRT) in CRC that phosphorylated Y88 in paxillin impacts the AKT pathway by controlling the interaction of the p85 regulatory PI3K subunit and p130Cas [26]. In a recent study, cysteine-rich protein 2 (CSRP2) was shown to inhibit p130Cas phosphorylation and subsequent Rac family small GTPase 1 (Rac 1) activation, thereby increasing the activity of the Hippo pathway and decreasing the p21-activated kinase (PAK)-cortactin and MAPK pathways [27]. This resulted in suppressed EMT in vitro and reduced tumorigenicity and metastasis of CRC in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…We previously identified a potential association of BCAR1 expression with CRC [23]. Other studies showed the involvement of p130Cas in α1-integrin/c-Src-mediated invasion of CRC cells [24], in c-Src regulated PI3K/AKT-driven colon tumorigenesis [25,26], and cysteine-rich protein 2 (CSRP2) controlled suppression of CRC progression [27].…”

Section: Introductionmentioning

confidence: 99%

p130Cas Is Correlated with EREG Expression and a Prognostic Factor Depending on Colorectal Cancer Stage and Localization Reducing FOLFIRI Efficacy

Kumbrink

Pók-Udvari

et al. 2021

IJMS

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p130 Crk-associated substrate (p130Cas) is associated with poor prognosis and treatment resistance in breast and lung cancers. To elucidate p130Cas functional and clinical role in colorectal cancer (CRC) progression/therapy resistance, we performed cell culture experiments and bioinformatic/statistical analyses of clinical data sets. p130Cas expression was associated with poor survival in the cancer genome atlas (TCGA) data set. Knockdown/reconstitution experiments showed that p130Cas drives migration but, unexpectedly, inhibits proliferation in CRC cells. TCGA data analyses identified the growth factor epiregulin (EREG) as inversely correlated with p130Cas. p130Cas knockdown and simultaneous EREG treatment further enhanced proliferation. RNA interference and EREG treatment experiments suggested that p130Cas/EREG limit each other’s expression/activity. Inverse p130Cas/EREG Spearman correlations were prominent in right-sided and earlier stage CRC. p130Cas was inducible by 5-fluorouracil (5-FU) and FOLFIRI (folinic acid, 5-FU, irinotecan), and p130Cas and EREG were upregulated in distant metastases (GSE121418). Positive p130Cas/EREG correlations were observed in metastases, preferentially in post-treatment samples (especially pulmonary metastases). p130Cas knockdown sensitized CRC cells to FOLFIRI independent of EREG treatment. RNA sequencing and gene ontology analyses revealed that p130Cas is involved in cytochrome P450 drug metabolism and epithelial-mesenchymal transition. p130Cas expression was associated with poor survival in right-sided, stage I/II, MSS (microsatellite stable), or BRAF-mutated CRC. In summary, p130Cas represents a prognostic factor and potential therapeutic target in CRC.

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“…Taking advantage of in vivo experiments, it was shown that thiopurines treatments (TG) inhibited CAC in the AOM/DSS mouse model, via decreased β-catenin in a RAC1-dependent mechanism [ 144 ]. In the context of epithelial cell targeting, EMT and metastatic potential might be inhibited upon activation of RAC1; for instance, upon CSRP2 treatment (Hippo-ERK-PAK/LIMK/cortactin) [ 145 ], miR-142-3p transfection [ 146 ], upregulation of SSH3 (LIMK) [ 147 ] or PLS1 (ERK1/2) [ 148 ], downregulation of DMTN [ 149 ], or IRF1 suppression [ 150 ]. Recent work from An et al revealed the different behavior of RAC1 inhibition in combination with irradiation on cell cycle.…”

Section: Rac1 (Ras-related C3 Botulinum Toxin Substrate 1)mentioning

confidence: 99%

Rho GTPases as Key Molecular Players within Intestinal Mucosa and GI Diseases

Pradhan

Ngo

Martínez-Sánchez

et al. 2021

Cells

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Rho proteins operate as key regulators of the cytoskeleton, cell morphology and trafficking. Acting as molecular switches, the function of Rho GTPases is determined by guanosine triphosphate (GTP)/guanosine diphosphate (GDP) exchange and their lipidation via prenylation, allowing their binding to cellular membranes and the interaction with downstream effector proteins in close proximity to the membrane. A plethora of in vitro studies demonstrate the indispensable function of Rho proteins for cytoskeleton dynamics within different cell types. However, only in the last decades we have got access to genetically modified mouse models to decipher the intricate regulation between members of the Rho family within specific cell types in the complex in vivo situation. Translationally, alterations of the expression and/or function of Rho GTPases have been associated with several pathological conditions, such as inflammation and cancer. In the context of the GI tract, the continuous crosstalk between the host and the intestinal microbiota requires a tight regulation of the complex interaction between cellular components within the intestinal tissue. Recent studies demonstrate that Rho GTPases play important roles for the maintenance of tissue homeostasis in the gut. We will summarize the current knowledge on Rho protein function within individual cell types in the intestinal mucosa in vivo, with special focus on intestinal epithelial cells and T cells.

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CSRP2 suppresses colorectal cancer progression via p130Cas/Rac1 axis-meditated ERK, PAK, and HIPPO signaling pathways

Cited by 27 publications

References 55 publications

BCAR1 plays critical roles in the formation and immunoevasion of invasive circulating tumor cells in lung adenocarcinoma

BCAR1 plays critical roles in the formation and immunoevasion of invasive circulating tumor cells in lung adenocarcinoma

p130Cas Is Correlated with EREG Expression and a Prognostic Factor Depending on Colorectal Cancer Stage and Localization Reducing FOLFIRI Efficacy

Rho GTPases as Key Molecular Players within Intestinal Mucosa and GI Diseases

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