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Role of SMC1A overexpression as a predictor of poor prognosis in late stage colorectal cancer.

Wang J, Yu S, Cui L, Wang W, Li J, Wang K, Lao X - BMC Cancer (2015)

Bottom Line: Recent studies have concluded that SMC1A is involved in the pathogenesis of cancer.Functional analysis indicated that SMC1A knockdown by small interfering RNA (siRNA) mediated the significant inhibition of cell proliferation; induced cell cycle arrest and apoptosis via the suppression of CDK4, PCNA and PARP; and blocked the activation of the Erk1/2 and Akt cascades in CRC cells.These results suggest that SMC1A plays an essential role in the development of CRC and may be a predictive factor in patients with CRC.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China. jianweidr@163.com.

ABSTRACT

Background: Structural maintenance of chromosomes 1A (SMC1A) is a member of the cohesion family of proteins that plays crucial roles in cell cycle control. Recent studies have concluded that SMC1A is involved in the pathogenesis of cancer. This study aims to evaluate the functional role of SMC1A in colorectal cancer (CRC) both in vitro and in vivo, and the underlying molecular mechanisms.

Methods: We firstly investigated the expression levels of SMC1A in 427 CRC specimens. Antigen expression was determined by immunohistochemical analysis of SMC1A on tissue microarrays. Stable SMC1A knockdown CRC cell lines were employed. The effects of SMC1A depletion on cell growth in vitro were examined by MTT, colony formation and flow cytometry assays. Tumor forming was evaluated by nude mice model in vivo. To detect the activation of intracellular signaling, pathscan intracellular signaling array and western blotting were performed.

Results: The expression of SMC1A was much stronger in CRC tumor tissues than in adenomas and normal colorectal tissues. High SMC1A expression, indicated as an independent poor prognostic predictor for patients with stage III and stage IV CRC, was correlated with overall survival (OS) (p = 0.008). Functional analysis indicated that SMC1A knockdown by small interfering RNA (siRNA) mediated the significant inhibition of cell proliferation; induced cell cycle arrest and apoptosis via the suppression of CDK4, PCNA and PARP; and blocked the activation of the Erk1/2 and Akt cascades in CRC cells. In addition, SMC1A depletion significantly decreased the growth of subcutaneously inoculated tumors in nude mice.

Conclusions: These results suggest that SMC1A plays an essential role in the development of CRC and may be a predictive factor in patients with CRC. The inhibition of SMC1A may serve as a promising therapeutic strategy for human CRC.

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Related in: MedlinePlus

Mechanism study of SMC1A silencing in CRC cells. (A) Intracellular signaling array after Lv-shSMC1A infection. (B) Western blotting analysis of SMC1A-related signaling molecules in RKO cells. (C) SignaLink 2.0 analysis of SMC1A-related signaling molecules in RKO cells.
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Fig4: Mechanism study of SMC1A silencing in CRC cells. (A) Intracellular signaling array after Lv-shSMC1A infection. (B) Western blotting analysis of SMC1A-related signaling molecules in RKO cells. (C) SignaLink 2.0 analysis of SMC1A-related signaling molecules in RKO cells.

Mentions: To investigate the regulatory mechanism of SMC1A in the tumorigenesis of CRC, multiple signaling pathways were analyzed in SW480 cells after SMC1A knockdown. SMC1A-triggered signal transduction was determined using the PathScan intracellular signaling array kit. Knockdown of SMC1A obviously inhibited the activation of Akt and induced the activation of PRAS40 (Figure 4A). Moreover, depletion of SMC1A significantly inhibited the phosphorylation of Erk1/2, indicating that SMC1A affected cell proliferation possibly via the tyrosine kinase-activated Ras/MEK/Erk pathway and Ras/PI3K/Akt pathway. In addition, SMC1A silencing decreased the expression levels of CDK4, PCNA and PARP in SW480 cells, indicating that CDK4, PCNA and PARP play important roles in SMC1A-induced cell cycle arrest and apoptosis (Figure 4B). Furthermore, a signaling pathway resource with multi-layered regulatory networks was applied to identify SMC1A-related signaling molecules (Figure 4C). Further studies are needed to clarify the mechanisms of SMC1A in CRC progression.Figure 4


Role of SMC1A overexpression as a predictor of poor prognosis in late stage colorectal cancer.

Wang J, Yu S, Cui L, Wang W, Li J, Wang K, Lao X - BMC Cancer (2015)

Mechanism study of SMC1A silencing in CRC cells. (A) Intracellular signaling array after Lv-shSMC1A infection. (B) Western blotting analysis of SMC1A-related signaling molecules in RKO cells. (C) SignaLink 2.0 analysis of SMC1A-related signaling molecules in RKO cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4352287&req=5

Fig4: Mechanism study of SMC1A silencing in CRC cells. (A) Intracellular signaling array after Lv-shSMC1A infection. (B) Western blotting analysis of SMC1A-related signaling molecules in RKO cells. (C) SignaLink 2.0 analysis of SMC1A-related signaling molecules in RKO cells.
Mentions: To investigate the regulatory mechanism of SMC1A in the tumorigenesis of CRC, multiple signaling pathways were analyzed in SW480 cells after SMC1A knockdown. SMC1A-triggered signal transduction was determined using the PathScan intracellular signaling array kit. Knockdown of SMC1A obviously inhibited the activation of Akt and induced the activation of PRAS40 (Figure 4A). Moreover, depletion of SMC1A significantly inhibited the phosphorylation of Erk1/2, indicating that SMC1A affected cell proliferation possibly via the tyrosine kinase-activated Ras/MEK/Erk pathway and Ras/PI3K/Akt pathway. In addition, SMC1A silencing decreased the expression levels of CDK4, PCNA and PARP in SW480 cells, indicating that CDK4, PCNA and PARP play important roles in SMC1A-induced cell cycle arrest and apoptosis (Figure 4B). Furthermore, a signaling pathway resource with multi-layered regulatory networks was applied to identify SMC1A-related signaling molecules (Figure 4C). Further studies are needed to clarify the mechanisms of SMC1A in CRC progression.Figure 4

Bottom Line: Recent studies have concluded that SMC1A is involved in the pathogenesis of cancer.Functional analysis indicated that SMC1A knockdown by small interfering RNA (siRNA) mediated the significant inhibition of cell proliferation; induced cell cycle arrest and apoptosis via the suppression of CDK4, PCNA and PARP; and blocked the activation of the Erk1/2 and Akt cascades in CRC cells.These results suggest that SMC1A plays an essential role in the development of CRC and may be a predictive factor in patients with CRC.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China. jianweidr@163.com.

ABSTRACT

Background: Structural maintenance of chromosomes 1A (SMC1A) is a member of the cohesion family of proteins that plays crucial roles in cell cycle control. Recent studies have concluded that SMC1A is involved in the pathogenesis of cancer. This study aims to evaluate the functional role of SMC1A in colorectal cancer (CRC) both in vitro and in vivo, and the underlying molecular mechanisms.

Methods: We firstly investigated the expression levels of SMC1A in 427 CRC specimens. Antigen expression was determined by immunohistochemical analysis of SMC1A on tissue microarrays. Stable SMC1A knockdown CRC cell lines were employed. The effects of SMC1A depletion on cell growth in vitro were examined by MTT, colony formation and flow cytometry assays. Tumor forming was evaluated by nude mice model in vivo. To detect the activation of intracellular signaling, pathscan intracellular signaling array and western blotting were performed.

Results: The expression of SMC1A was much stronger in CRC tumor tissues than in adenomas and normal colorectal tissues. High SMC1A expression, indicated as an independent poor prognostic predictor for patients with stage III and stage IV CRC, was correlated with overall survival (OS) (p = 0.008). Functional analysis indicated that SMC1A knockdown by small interfering RNA (siRNA) mediated the significant inhibition of cell proliferation; induced cell cycle arrest and apoptosis via the suppression of CDK4, PCNA and PARP; and blocked the activation of the Erk1/2 and Akt cascades in CRC cells. In addition, SMC1A depletion significantly decreased the growth of subcutaneously inoculated tumors in nude mice.

Conclusions: These results suggest that SMC1A plays an essential role in the development of CRC and may be a predictive factor in patients with CRC. The inhibition of SMC1A may serve as a promising therapeutic strategy for human CRC.

Show MeSH
Related in: MedlinePlus