Prognostic role of p27<sup>Kip1</sup> deregulation in colorectal cancer

Hershko, Dan; Shapira, Maanit

doi:10.1002/cncr.22073

Cited by 63 publications

(59 citation statements)

References 52 publications

(68 reference statements)

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“…Kip1 has a profound effect on tumor progression in colorectal cancer and is suggested to be an accurate and independent prognostic marker [30] . Moreover, p27…”

Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor regulatesproliferation of gastric cancer cellsvia the PI3K/Akt pathway

Li¹,

Xie²,

Lei³

et al. 2009

WJG

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AIM:To investigate the effects of macrophage migration inhibitory factor (MIF) on proliferation of human gastric cancer MGC-803 cells and expression of cyclin D1 and p27Kip1 in them, and further determine whether the effects are related to the PI3K/Akt signal transduction pathway. METHODS:Gastric cancer MGC-803 cells were cultured and then treated with 50 μg/L recombinant human MIF (rhMIF) with and without a PI3K inhibitor, LY294002 (25 μmol/L). MTT assay was used to detect the proliferation of MGC-803 cells. Cell cycle was detected by flow cytometry. Expression of cyclin D1 and p27Kip1 mRNA was by reverse transcription-polymerase chain reaction. Protein expression of phosphorylated Akt (p-Akt), Akt, cyclin D1 and p27Kip1 was examined by immunocytochemistry and Western blotting.RESULTS: rhMIF significantly stimulated the proliferation of MGC-803 cells and cell cycle progression from G1 phase to S phase in a concentration-and time-dependent manner. After the MGC-803 cells were treated with rhMIF for 24 h, the expression of cyclin D1 was significantly up-regulated compared with the cells not treated with rhMIF at both mRNA and protein levels (0.97 ± 0.02 vs 0.74 ± 0.01, P = 0.002; 0.98 ± 0.05 vs 0.69 ± 0.04, P = 0.003). The p27Kip1 was downregulated but only statistically significant at the protein level. rhMIF significantly increased the expression of p-Akt, which reached the peak at 30 min, but did not affect the expression of Akt. However, LY294002 inhibited all the effects of rhMIF. CONCLUSION:Macrophage MIF increases the proliferation of gastric cancer cells, induces the expression of cyclin D1 at the transcriptional level and inhibits the expression of p27Kip1 at the post-transcriptional level via the PI3K/Akt pathway.

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“…Kip1 has a profound effect on tumor progression in colorectal cancer and is suggested to be an accurate and independent prognostic marker [30] . Moreover, p27…”

Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor regulatesproliferation of gastric cancer cellsvia the PI3K/Akt pathway

Li¹,

Xie²,

Lei³

et al. 2009

WJG

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“…28 In addition, p27 plays an important role in cellular proliferation and differentiation and appears to act as a tumor suppressor gene. Several studies have reported a significant association between loss of p27 expression and worse prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have reported a significant association between loss of p27 expression and worse prognosis. 28,29 In addition, evidence suggests that the prognostic significance of p27 may be related to early-stage CRC. 30,31 Our results are in line with these findings, because we demonstrated that the loss of p27 expression was linked to a significantly worse prognosis in both univariate analysis and multivariate analysis with CD8 and uPA.…”

Section: Discussionmentioning

confidence: 99%

Multimarker phenotype predicts adverse survival in patients with lymph node‐negative colorectal cancer

Zlobec

Minoo

Baumhoer

et al. 2007

Cancer

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BACKGROUND. The heterogeneity of stage II colon cancer underlines the need for identifying high‐risk, lymph node‐negative patients. The objective of this study was to define a multimarker prognostic model of 5‐year survival in patients with lymph node‐negative, mismatch repair (MMR)‐proficient colorectal cancer (CRC). METHODS. Immunohistochemistry for 13 tumor markers was performed on 587 lymph node‐negative, MMR‐proficient CRC samples by using a tissue microarray. Immunoreactivity was evaluated semiquantitatively. A receiver‐operating characteristic‐based approach was used to detect clinically relevant tumor markers and to determine cutoff scores for tumor positivity. Univariate and multivariate analyses stratified by pathologic T3 (pT3) or pT4 tumor classification were performed. RESULTS. In univariate analysis, the absence of CD8+ tumor infiltrating lymphocytes (TILs) (P < .001), loss of p27 (P = .006), positive urokinase‐type plasminogen activator (uPA) expression (P = .002), and positive uPA receptor (uPAR) expression (P = .037) were associated with an adverse prognosis. In multivariate analysis, CD8 (P = .001), p27 (P = .031), and uPA (P = .014) were independent prognostic factors. The multimarker phenotype of negative CD8, loss of p27, and positive uPA expression led to significantly worse survival compared with all other combinations of these features. Stratified by pT3 or pT4 stage, CD8 (P = .006) and uPA (P = .011) had independent prognostic value. Combined CD8 negativity and uPA positivity led to a more adverse prognosis in both patients with pT3 tumors and patients with pT4 tumors (P < .001). No difference was observed in the length of survival between patients with pT3 tumors who had CD8 negativity and uPA positivity and patients with pT4 tumors (P = .267). CONCLUSIONS. The multimarker phenotype of the absence of CD8+ TILs, loss of p27, and positive uPA expression was predictive of an adverse prognosis in patients with lymph node‐negative, MMR‐proficient CRC. The current findings suggested that a subgroup of patients with high‐risk, lymph node‐negative pT3 tumors should be considered for adjuvant therapy. Cancer 2008. © 2007 American Cancer Society.

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“…For example, in colorectal and oral cancers, Skp2 was reported to have a profound effect on tumor progression and to be an accurate and independent prognostic marker. [11][12][13] Previous studies have lent further credence to this mutual yet reciprocal role of the expression rates of Skp2 and p27 in salivary cancer, supporting the hypothesis that Skp2, the specific recognition factor for p27 ubiquitination, has oncogenic properties. Kaplan-Meier analysis showed significantly poorer survival in patients with enhanced Skp2 (>4%) and reduced p27 (≤50%) stained tumors.…”

Section: Discussionmentioning

confidence: 78%

Skp2 and salivary cancer

Ben‐Izhak

Akrish²,

Gan³

et al. 2009

Cancer Biology & Therapy

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Salivary malignancies are rare, heterogeneous, unpredictable in clinical behavior and seldom studied. Skp2 expression was examined in salivary malignancies (n = 75) for a prolonged period (20 years). In 40/75 (53%) cases Skp2 expression rate (staining level) was ≤4% while in the remainder (47%) it was >4%. Correlation between enhanced Skp2 and enhanced p53 staining levels was significant (p = 0.042), as were correlation rates between enhanced Skp2 and reduced p27 staining levels (p = 0.01) and enhanced Skp2 and enhanced TUNEL staining levels (p = 0.008). Survival probability rates dropped when Skp2 expression increased. Median patient survival for reduced-stained-tumor patients (≤4%) was 143 months and significantly lower, 49 months (p = 0.016), for enhanced-stained-tumor patients (>4%). Survival probability at five years was 82% for the former group (≤4%) and 47% for the latter (>4%). At 20 years, survival dropped to 35% and 18% respectively (p = 0.016). More extensive and aggressive therapy did not reduce mortality in patients with enhanced Skp2-expressing tumors. Significant correlations between poor survival and significantly altered expression rates of Skp2, p27, p53, TUNEL and heparanase in salivary malignancies, suggest a biological role in salivary cancer pathogenesis for these five markers. The findings may be used for prognostic and follow-up purposes.

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Prognostic role of p27^Kip1 deregulation in colorectal cancer

Cited by 63 publications

References 52 publications

Macrophage migration inhibitory factor regulatesproliferation of gastric cancer cellsvia the PI3K/Akt pathway

Macrophage migration inhibitory factor regulatesproliferation of gastric cancer cellsvia the PI3K/Akt pathway

Multimarker phenotype predicts adverse survival in patients with lymph node‐negative colorectal cancer

Skp2 and salivary cancer

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Prognostic role of p27Kip1 deregulation in colorectal cancer

Cited by 63 publications

References 52 publications

Macrophage migration inhibitory factor regulatesproliferation of gastric cancer cellsvia the PI3K/Akt pathway

Macrophage migration inhibitory factor regulatesproliferation of gastric cancer cellsvia the PI3K/Akt pathway

Multimarker phenotype predicts adverse survival in patients with lymph node‐negative colorectal cancer

Skp2 and salivary cancer

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Prognostic role of p27^Kip1 deregulation in colorectal cancer