Role of SSH1 in colorectal cancer prognosis and tumor progression

Song, Xiangping; Xie, Di; Xiao, Xianmin; Tan, Fengbo; Pei, Qian; Li, Yuqiang; Zhou, Zhongyi; Zhou, Yuan; Li, Chenglong; Wang, Kangtao; Pei, Haiping

doi:10.1111/jgh.15001

Cited by 7 publications

(9 citation statements)

References 28 publications

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“…CMS1 subtype have the worst survival after relapse while CMS4 exhibits the worst prognosis subtype [2]. In agreement with our results, previous reports have shown a relevant association between these proteins and EMT markers [E-cadherin, β-catenin (nuclear), ZEB1, and SNAIL] in CRC tissues [19,21], indicating their central role during EMT in CRC. We previously demonstrated, using an in vitro model, the dynamic role of CFL-1 and LIMK2 during EMT in CRC [25].…”

Section: Discussionsupporting

confidence: 92%

“…Indeed, in our clinical cohort, some patients showed low expression of CFL-1 and SSH1 mRNA. Conversely, the upregulation of SSH1 mRNA levels has been observed in CRC tumor tissues when compared with control tissues, and was also associated with tumor stage, lymph node metastasis, and poor prognosis [21]. In addition, SSH1 upregulation was also observed in breast and pancreatic tumors.…”

Section: Discussionmentioning

confidence: 97%

“…In the case of CRC, CFL-1 gene expression information is limited and divergent. Some studies have demonstrated elevated gene and protein expression, while others showed decreased expression in relation to normal tissues [17][18][19][20][21].…”

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confidence: 99%

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Cofilin-1, LIMK1 and SSH1 are differentially expressed in locally advanced colorectal cancer and according to consensus molecular subtypes

et al. 2021

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Background Colorectal cancer (CRC) is among the deadliest cancers, wherein early dissemination of tumor cells, and consequently, metastasis formation, are the main causes of mortality and poor prognosis. Cofilin-1 (CFL-1) and its modulators, LIMK1/SSH1, play key roles in mediating the invasiveness by driving actin cytoskeleton reorganization in various cancer types. However, their clinical significance and prognostic value in CRC has not been fully explored. Here, we evaluated the clinical contribution of these actin regulators according to TNM and consensus molecular subtypes (CMSs) classification. Methods CFL-1, LIMK1 and SSH1 mRNA/protein levels were assessed by real-time PCR and immunohistochemical analyses using normal adjacent and tumor tissues obtained from a clinical cohort of CRC patients. The expression levels of these proteins were associated with clinicopathological features by using the chi square test. In addition, using RNA-Seq data of CRC patients from The Cancer Genome Atlas (TCGA) database, we determine how these actin regulators are expressed and distributed according to TNM and CMSs classification. Based on gene expression profiling, Kaplan–Meier survival analysis was used to evaluated overall survival. Results Bioinformatic analysis revealed that LIMK1 expression was upregulated in all tumor stages. Patients with high levels of LIMK1 demonstrated significantly lower overall survival rates and exhibited greater lymph node metastatic potential in a clinical cohort. In contrast, CFL-1 and SSH1 have expression downregulated in all tumor stages. However, immunohistochemical analyses showed that patients with high protein levels of CFL-1 and SSH1 exhibited greater lymph node metastatic potential and greater depth of local invasion. In addition, using the CMSs classification to evaluate different biological phenotypes of CRC, we observed that LIMK1 and SSH1 genes are upregulated in immune (CMS1) and mesenchymal (CMS4) subtypes. However, patients with high levels of LIMK1 also demonstrated significantly lower overall survival rates in canonical (CMS2), and metabolic (CMS3) subtypes. Conclusions We demonstrated that CFL-1 and its modulators, LIMK1/SSH1, are differentially expressed and associated with lymph node metastasis in CRC. Finally, this expression profile may be useful to predict patients with aggressive signatures, particularly, the immune and mesenchymal subtypes of CRC.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 97%

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Cofilin-1, LIMK1 and SSH1 are differentially expressed in locally advanced colorectal cancer and according to consensus molecular subtypes

et al. 2021

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“…The SSH proteins are a family of phosphatases playing a role in actin dynamics by activating cofilin [ 17 ]. Interestingly, SSH1 expression was recently associated with colon cancer progression through regulation of the epithelial to mesenchymal transition [ 30 ]. Furthermore, patients with elevated SSH1 levels have been shown to exhibit greater lymph node invasion [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Paladin, overexpressed in colon cancer, is required for actin polymerisation and liver metastasis dissemination

et al. 2022

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Introduction Colorectal cancer remains a public health issue and most colon cancer patients succumb to the development of metastases. Using a specific protocol of pressure-assisted interstitial fluid extrusion to recover soluble biomarkers, we identified paladin as a potential colon cancer liver metastases biomarker. Methods Using shRNA gene knockdown, we explored the biological function of paladin in colon cancer cells and investigated the phospho-proteome within colon cancer cells. We successively applied in vitro migration assays, in vivo metastasis models and co-immunoprecipitation experiments. Results We discovered that paladin is required for colon cancer cell migration and metastasis, and that paladin depletion altered the phospho-proteome within colon cancer cells. Data are available via ProteomeXchange with identifier PXD030803. Thanks to immunoprecipitation experiments, we demonstrated that paladin, was interacting with SSH1, a phosphatase involved in colon cancer metastasis. Finally, we showed that paladin depletion in cancer cells results in a less dynamic actin cytoskeleton. Conclusions Paladin is an undervalued protein in oncology. This study highlights for the first time that, paladin is participating in actin cytoskeleton remodelling and is required for efficient cancer cell migration.

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“…Immunohistochemistry staining was performed as previously described [ 3 , 16 ]. Briefly, the sections were dewaxed and rehydrated.…”

Section: Methodsmentioning

confidence: 99%

Intravascular emboli relates to immunosuppressive tumor microenvironment and predicts prognosis in stage III colorectal cancer

Song

Xie

Tan

et al. 2021

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Background: Stage III colorectal cancer (CRC) patients experience varying degrees of prognosis even if receiving standard therapeutic regimes. Intravascular emboli (IVE), a type of vascular invasion, impacts the clinical outcome in CRC. In this study, we confirmed the role of IVE in predicting the prognosis of stage III CRC patients and characterized the tumor microenvironment (TME) of CRC with IVE. Methods: Data from 220 consecutive patients (cohort 1) with stage III CRC undergoing radical surgery was collected retrospectively between January 2009 to December 2014. According to the presence of IVE, which was confirmed by two independent pathologists, patients were classified into two groups. Univariate and multivariate Cox regression analyses were performed to evaluate the relation of IVE presence to patients’ prognosis. The association between IVE and clinicopathological factors was also analyzed. Furthermore, differentially expressed genes (DEGs) and gene set enrichment analyses (GSEA) were performed to describe features of the TME based on microarray data consisting of 6 patients. Tumor tissues from a separate cohort of 73 patients with stage III CRC (cohort 2) collected between June 2014 and December 2015 were used to analyze tumor-infiltrating lymphocyte (TIL) by immunohistochemistry (IHC) staining. Results: IVE was observed in 126 (57.3%) patients and could serve as an unfavorable independent prognostic predictor (P < 0.001) as well as lymph node metastasis (P < 0.05) and tumor location (P < 0.05). Additionally, patients with IVE had a higher neutrophil percentage (P = 0.002) and lower lymphocyte percentage (P = 0.002) relative to those without IVE. CRC with IVE had a significantly different profile of DEGs compared to CRC without IVE, and GSEA showed chronic inflammatory and immunosuppressive TME may promote IVE development. In cohort 2, tumors with IVE had fewer CD3 + TILs in the stromal region, as well as fewer CD8 + TILs in both stromal and tumoral regions relative to those without IVE. Conclusion: IVE, which was related closely to a chronic inflammatory and immunosuppressive TME, forecasted a worse prognosis of stage III CRC patients and may be taken into consideration when a therapeutic strategy is decided upon.

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Role of SSH1 in colorectal cancer prognosis and tumor progression

Cited by 7 publications

References 28 publications

Cofilin-1, LIMK1 and SSH1 are differentially expressed in locally advanced colorectal cancer and according to consensus molecular subtypes

Cofilin-1, LIMK1 and SSH1 are differentially expressed in locally advanced colorectal cancer and according to consensus molecular subtypes

Paladin, overexpressed in colon cancer, is required for actin polymerisation and liver metastasis dissemination

Intravascular emboli relates to immunosuppressive tumor microenvironment and predicts prognosis in stage III colorectal cancer

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