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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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Effect of SMC1A silencing on the tumorigenesis of CRC in vivo. (A) The subcutaneous xenograft murine model. (B) Representative images of tumors formed in the mice in which Lv-shSMC1A- or Lv-shCon-infected RKO cells were implanted. (C) Changes in the tumor volume on the 6th, 9th, 12th, 15th and 21st days after the cells were implanted subcutaneously. (D) Changes in the tumor weight in mice after SMC1A silencing. (E) Expression analysis of SMC1A in tumor tissues collected from mice. ***p < 0.01 in comparison with non-silencing shRNA infected control.
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Fig3: Effect of SMC1A silencing on the tumorigenesis of CRC in vivo. (A) The subcutaneous xenograft murine model. (B) Representative images of tumors formed in the mice in which Lv-shSMC1A- or Lv-shCon-infected RKO cells were implanted. (C) Changes in the tumor volume on the 6th, 9th, 12th, 15th and 21st days after the cells were implanted subcutaneously. (D) Changes in the tumor weight in mice after SMC1A silencing. (E) Expression analysis of SMC1A in tumor tissues collected from mice. ***p < 0.01 in comparison with non-silencing shRNA infected control.

Mentions: The effects of SMC1A silencing on the development of colon tumors were analyzed in vivo using nude mouse models. As shown in Figure 3A and B, the size of the tumors was significantly decreased after SMC1A knockdown in a time course of 20 days. Moreover, the time-dependent analysis showed that the development of tumors peaked after 15 days, and the volume of the tumors was significantly suppressed in mice inoculated with SMC1A-silenced RKO cells compared with control groups (Figure 3C). Furthermore, the weight of the tumors was also remarkably decreased (p < 0.001) in SMC1A-silenced mice (Figure 3D). These results were confirmed by analysis of the protein content of SMC1A in tissues of a subcutaneous xenograft murine model. The SMC1A expression level was completely suppressed in tumor tissues by the infection with SMC1A shRNA (Figure 3E). This finding indicated that colon tumorigenesis was significantly inhibited by the absence of SMC1A.Figure 3


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)

Effect of SMC1A silencing on the tumorigenesis of CRC in vivo. (A) The subcutaneous xenograft murine model. (B) Representative images of tumors formed in the mice in which Lv-shSMC1A- or Lv-shCon-infected RKO cells were implanted. (C) Changes in the tumor volume on the 6th, 9th, 12th, 15th and 21st days after the cells were implanted subcutaneously. (D) Changes in the tumor weight in mice after SMC1A silencing. (E) Expression analysis of SMC1A in tumor tissues collected from mice. ***p < 0.01 in comparison with non-silencing shRNA infected control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: Effect of SMC1A silencing on the tumorigenesis of CRC in vivo. (A) The subcutaneous xenograft murine model. (B) Representative images of tumors formed in the mice in which Lv-shSMC1A- or Lv-shCon-infected RKO cells were implanted. (C) Changes in the tumor volume on the 6th, 9th, 12th, 15th and 21st days after the cells were implanted subcutaneously. (D) Changes in the tumor weight in mice after SMC1A silencing. (E) Expression analysis of SMC1A in tumor tissues collected from mice. ***p < 0.01 in comparison with non-silencing shRNA infected control.
Mentions: The effects of SMC1A silencing on the development of colon tumors were analyzed in vivo using nude mouse models. As shown in Figure 3A and B, the size of the tumors was significantly decreased after SMC1A knockdown in a time course of 20 days. Moreover, the time-dependent analysis showed that the development of tumors peaked after 15 days, and the volume of the tumors was significantly suppressed in mice inoculated with SMC1A-silenced RKO cells compared with control groups (Figure 3C). Furthermore, the weight of the tumors was also remarkably decreased (p < 0.001) in SMC1A-silenced mice (Figure 3D). These results were confirmed by analysis of the protein content of SMC1A in tissues of a subcutaneous xenograft murine model. The SMC1A expression level was completely suppressed in tumor tissues by the infection with SMC1A shRNA (Figure 3E). This finding indicated that colon tumorigenesis was significantly inhibited by the absence of SMC1A.Figure 3

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