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Levels of human replication factor C4, a clamp loader, correlate with tumor progression and predict the prognosis for colorectal cancer.

Xiang J, Fang L, Luo Y, Yang Z, Liao Y, Cui J, Huang M, Yang Z, Huang Y, Fan X, Wang H, Wang L, Peng J, Wang J - J Transl Med (2014)

Bottom Line: RFC4 expression was significantly increased in CRC specimens as compared to adjacent normal colonic tissues (P <0.05).High levels of RFC4, determined on a tissue microarray, were significantly associated with differentiation, an advanced stage by the Tumor-Node-Metastasis (TNM) staging system, and a poor prognosis, as compared to low levels of expression (P <0.05).RFC4 is frequently overexpressed in CRC, and is associated with tumor progression and worse survival outcome.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, China. xxj007@126.com.

ABSTRACT

Background: Human replication factor C4 (RFC4) is involved in DNA replication as a clamp loader and is aberrantly regulated across a range of cancers. The current study aimed to investigate the function of RFC4 in colorectal cancer (CRC).

Methods: The mRNA levels of RFC4 were assessed in 30 paired primary CRC tissues and matched normal colonic tissues by quantitative PCR. The protein expression levels of RFC4 were evaluated by western blotting (n = 16) and immunohistochemistry (IHC; n = 49), respectively. Clinicopathological features and survival data were correlated with the expression of RFC4 by IHC analysis in a tissue microarray comprising 331 surgically resected CRC. The impact of RFC4 on cell proliferation and the cell cycle was assessed using CRC cell lines.

Results: RFC4 expression was significantly increased in CRC specimens as compared to adjacent normal colonic tissues (P <0.05). High levels of RFC4, determined on a tissue microarray, were significantly associated with differentiation, an advanced stage by the Tumor-Node-Metastasis (TNM) staging system, and a poor prognosis, as compared to low levels of expression (P <0.05). However, in multivariate analysis, RFC4 was not an independent predictor of poor survival for CRC. In vitro studies, the loss of RFC4 suppressed CRC cell proliferation and induced S-phase cell cycle arrest.

Conclusion: RFC4 is frequently overexpressed in CRC, and is associated with tumor progression and worse survival outcome. This might be attributed to the regulation of CRC cell proliferation and cell cycle arrest by RFC4.

No MeSH data available.


Related in: MedlinePlus

Expression pattern of RFC4 in CRC by immunohistochemistry. The low power photomicrographs (left side) in each section show the full tissue spot (×100), while the high power photomicrographs (right side) show details of RFC4 expression (×400). Nuclear staining is considered RFC4 expression positive. (A) negative nuclear staining; (B) weak nuclear staining; (C) moderate nuclear staining; (D) strong nuclear staining.
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Fig2: Expression pattern of RFC4 in CRC by immunohistochemistry. The low power photomicrographs (left side) in each section show the full tissue spot (×100), while the high power photomicrographs (right side) show details of RFC4 expression (×400). Nuclear staining is considered RFC4 expression positive. (A) negative nuclear staining; (B) weak nuclear staining; (C) moderate nuclear staining; (D) strong nuclear staining.

Mentions: The potential significance of RFC4 protein levels in CRC was examined by IHC on the TMA consisting of tissues from 331 CRC tumors, which were divided into a normal expression group and an overexpression group based on the above cutoff value. Dichotomized groups were evaluated in relation to clinicopathologic factors and overall survival. The RFC4 IHC staining results are summarized in Table 2 and Figure 2. RFC4 expression positively correlated with differentiation and TNM stage (P <0.05; Table 2). Patients with poorly differentiated or advanced TNM stage CRC were frequently identified with RFC4 overexpression. No significant associations were noted between RFC4 expression and other clinicopathologic variables. In relation to clinical outcomes, high levels of RFC4 expression were significantly associated with poor OS and DFS by Kaplan-Meier analysis (Figure 3). The 5-year OS and 5-year DFS were 81% and 78%, respectively for normal RFC4 expression patients, while the high RFC4 expressing patients had 5-year OS and 5-year DFS of 67% and 65%, respectively. In addition, univariate analysis revealed that the extent of differentiation, CEA level, CA19-9 level, pN stage, pM stage, and RFC4 expression were risk factors for death in CRC. Further Multivariate analysis was performed using the Cox proportional hazards model for all of the significant variables in the univariate analysis, including differentiation, preoperative CEA level, preoperative CA19-9 level, TNM stage and RFC4 expression Table 3. The results showed that RFC4 expression was not an independent predictor of worse overall survival, which might attribute to that there were more stage III/IV patients (60.9%) having high expression levels of RFC4.Table 2


Levels of human replication factor C4, a clamp loader, correlate with tumor progression and predict the prognosis for colorectal cancer.

Xiang J, Fang L, Luo Y, Yang Z, Liao Y, Cui J, Huang M, Yang Z, Huang Y, Fan X, Wang H, Wang L, Peng J, Wang J - J Transl Med (2014)

Expression pattern of RFC4 in CRC by immunohistochemistry. The low power photomicrographs (left side) in each section show the full tissue spot (×100), while the high power photomicrographs (right side) show details of RFC4 expression (×400). Nuclear staining is considered RFC4 expression positive. (A) negative nuclear staining; (B) weak nuclear staining; (C) moderate nuclear staining; (D) strong nuclear staining.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4256821&req=5

Fig2: Expression pattern of RFC4 in CRC by immunohistochemistry. The low power photomicrographs (left side) in each section show the full tissue spot (×100), while the high power photomicrographs (right side) show details of RFC4 expression (×400). Nuclear staining is considered RFC4 expression positive. (A) negative nuclear staining; (B) weak nuclear staining; (C) moderate nuclear staining; (D) strong nuclear staining.
Mentions: The potential significance of RFC4 protein levels in CRC was examined by IHC on the TMA consisting of tissues from 331 CRC tumors, which were divided into a normal expression group and an overexpression group based on the above cutoff value. Dichotomized groups were evaluated in relation to clinicopathologic factors and overall survival. The RFC4 IHC staining results are summarized in Table 2 and Figure 2. RFC4 expression positively correlated with differentiation and TNM stage (P <0.05; Table 2). Patients with poorly differentiated or advanced TNM stage CRC were frequently identified with RFC4 overexpression. No significant associations were noted between RFC4 expression and other clinicopathologic variables. In relation to clinical outcomes, high levels of RFC4 expression were significantly associated with poor OS and DFS by Kaplan-Meier analysis (Figure 3). The 5-year OS and 5-year DFS were 81% and 78%, respectively for normal RFC4 expression patients, while the high RFC4 expressing patients had 5-year OS and 5-year DFS of 67% and 65%, respectively. In addition, univariate analysis revealed that the extent of differentiation, CEA level, CA19-9 level, pN stage, pM stage, and RFC4 expression were risk factors for death in CRC. Further Multivariate analysis was performed using the Cox proportional hazards model for all of the significant variables in the univariate analysis, including differentiation, preoperative CEA level, preoperative CA19-9 level, TNM stage and RFC4 expression Table 3. The results showed that RFC4 expression was not an independent predictor of worse overall survival, which might attribute to that there were more stage III/IV patients (60.9%) having high expression levels of RFC4.Table 2

Bottom Line: RFC4 expression was significantly increased in CRC specimens as compared to adjacent normal colonic tissues (P <0.05).High levels of RFC4, determined on a tissue microarray, were significantly associated with differentiation, an advanced stage by the Tumor-Node-Metastasis (TNM) staging system, and a poor prognosis, as compared to low levels of expression (P <0.05).RFC4 is frequently overexpressed in CRC, and is associated with tumor progression and worse survival outcome.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, China. xxj007@126.com.

ABSTRACT

Background: Human replication factor C4 (RFC4) is involved in DNA replication as a clamp loader and is aberrantly regulated across a range of cancers. The current study aimed to investigate the function of RFC4 in colorectal cancer (CRC).

Methods: The mRNA levels of RFC4 were assessed in 30 paired primary CRC tissues and matched normal colonic tissues by quantitative PCR. The protein expression levels of RFC4 were evaluated by western blotting (n = 16) and immunohistochemistry (IHC; n = 49), respectively. Clinicopathological features and survival data were correlated with the expression of RFC4 by IHC analysis in a tissue microarray comprising 331 surgically resected CRC. The impact of RFC4 on cell proliferation and the cell cycle was assessed using CRC cell lines.

Results: RFC4 expression was significantly increased in CRC specimens as compared to adjacent normal colonic tissues (P <0.05). High levels of RFC4, determined on a tissue microarray, were significantly associated with differentiation, an advanced stage by the Tumor-Node-Metastasis (TNM) staging system, and a poor prognosis, as compared to low levels of expression (P <0.05). However, in multivariate analysis, RFC4 was not an independent predictor of poor survival for CRC. In vitro studies, the loss of RFC4 suppressed CRC cell proliferation and induced S-phase cell cycle arrest.

Conclusion: RFC4 is frequently overexpressed in CRC, and is associated with tumor progression and worse survival outcome. This might be attributed to the regulation of CRC cell proliferation and cell cycle arrest by RFC4.

No MeSH data available.


Related in: MedlinePlus