Expressions of p27Kip1, RalA, and SPOCK1 in elderly colorectal cancer patients and relation between their expressions and prognosis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 HUANG Shanshan , ZHANG Jing , ZHAO Zhenwei , LIU Peng , ZHANG Yongjian , ZHANG Jiaqi

Department of General Surgery, Kailuan General Hospital Linxi Hospital, Tangshan, Hebei 063100, P. R. China;

Corresponding author：

HUANG Shanshan, Email: bdrxn1@163.com

Keywords：

elderly; colorectal cancer; p27Kip1; RalA; SPOCK1; prognosis

DOI：

10.7507/1007-9424.202411116

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Objective To explore the expressions of P27Kip1, RalA, and SPOCK1 in cancer tissues of the elderly patients with colorectal cancer (CRC) and the relations between their expressions and clinical pathological characteristics as well as prognosis. Methods The clinicopathologic data of elderly CRC patients treated and underwent surgical resection in Kailuan General Hospital Linxi Hospital from May 2019 to May 2022 were collected in a retrospective manner. The immunohistochemistry was used to detect the expressions of P27Kip1, RalA, and SPOCK1 proteins in the CRC tissues and corresponding adjacent tissues. The Kaplan-Meier method was applied to analyze the survival of CRC patients with p27Kip1, RalA, and SPOCK1 positive and negative expressions. The multivariate Cox risk regression model was applied to analyze the influencing factors of prognosis in the patients with CRC. The test level was set as α=0.05. Results A total of 149 elderly CRC patients were enrolled. All patients were followed up for 2 years, and 45 cases died of cancer during the follow-up period. The positive rate of p27Kip1 protein expression in the CRC tissues was lower than that in the corresponding adjacent tissues (P<0.05), while the positive rates of RalA and SPOCK1 protein expressions were higher than those in the corresponding adjacent tissues (P<0.05). The proportions of mucinous carcinoma, TNM stages Ⅲ–Ⅳ, low differentiation, positive lymph node metastasis, and T staging T2–T4 in the patients with negative p27Kip1 and positive RalA and SPOCK1 expressions were higher than those in the patients with positive p27Kip1 and negative RalA and SPOCK1 expressions (P<0.05). The proportions of patients with TNM stages Ⅲ–Ⅳ, negative p27Kip1 and positive RalA and SPOCK1 expressions in the death group were higher than that in the survival group (P<0.05). The survival curves plotted by the Kaplan-Meier method showed that the survival curves of patients with positive expression of p27Kip1 and negative expression of RalA and SPOCK1 in the cancer tissues were significantly better than those with negative expression of p27Kip1 and positive expression of RalA and SPOCK1 (respectively: log-rank χ²=11.678, P=0.001; log-rank χ²=10.836, P=0.001; log-rank χ²=10.792, P=0.001). The multivariate Cox proportional hazards regression model analysis revealed that the negative expression of p27Kip1 [HR(95%CI)=2.807(1.490, 5.287)], positive expression of RalA [HR(95%CI)=2.769(1.493, 5.134)], and positive expression of SPOCK1 [HR(95%CI)=3.075(1.610, 5.871)] were independent risk factors for postoperative mortality in CRC patients. Conclusion The results of this study suggest that the positive rate of p27Kip1 protein expression is low in CRC tissues, while the positive rates of RalaA and SPOCK1 protein expression are high, and the protein expression of these three indicators are associated with tissue type, TNM stage, degree of differentiation, lymph node metastasis, and T stage. Negative expression of p27Kip1 and positive expression of RalA and SPOCK1 are unfavorable for the prognosis of CRC patients.

1.	黄理宾, 黄秋实, 杨烈. 全球及中国的结直肠癌流行病学特征及防治: 2022《全球癌症统计报告》解读. 中国普外基础与临床杂志, 2024, 31(5): 530-537.
2.	1Ionescu VA, Gheorghe G, Bacalbasa N, et al. Colorectal cancer: From risk factors to oncogenesis. Medicina (Kaunas), 2023, 59(9): 1646. doi: 10.3390/medicina59091646.
3.	Oliveres H, Cascante M, Maurel J. Metabolic interventions to enhance immunotherapy and targeted therapy efficacy in advanced colorectal cancer. Curr Opin Chem Biol, 2023 Dec: 77: 102401.
4.	Goyal R, Wassie MM, Winter JM, et al. Progress in the field of noninvasive diagnostics for colorectal cancer: a systematic review for the accuracy of blood-based biomarkers for detection of advanced pre-cancerous lesions. Expert Rev Mol Diagn, 2023, 23(12): 1233-1250.
5.	Liu M, Xu X, Peng K, et al. Heparanase modulates the prognosis and development of BRAF V600E-mutant colorectal cancer by regulating AKT/p27Kip1/Cyclin E2 pathway. Oncogenesis, 2022, 11(1): 58.
6.	Ushigome M, Shimada H, Nabeya Y, et al. Possible predictive significance of serum RalA autoantibodies on relapse-free survival in patients with colorectal cancer. Mol Clin Oncol, 2021, 14(1): 18. doi: 10.3892/mco.2020.2180.
7.	Qu YL, Liu XL, Zhao SY, et al. SPOCK1 silencing decreases 5-FU resistance through PRRX1 in colorectal cancer. Pathol Res Pract, 2022, 234: 153895. doi: 10.1016/j.prp.2022.153895.
8.	中华人民共和国卫生和计划生育委员会医政医管局, 中华医学会肿瘤学分会. 中国结直肠癌诊疗规范(2017年版). 中华外科杂志, 2018, 56(4): 241-258.
9.	Murphy CC, Zaki TA. Changing epidemiology of colorectal cancer—birth cohort effects and emerging risk factors. Nat Rev Gastroenterol Hepatol, 2024, 21(1): 25-34.
10.	Song M, Chan AT, Sun J. Influence of the gut microbiome, diet, and environment on risk of colorectal cancer. Gastroenterology, 2020, 158(2): 322-340.
11.	Zhang D, Wu P, Zhang Z, et al. Overexpression of negative regulator of ubiquitin-like proteins 1 (NUB1) inhibits proliferation and invasion of gastric cancer cells through upregulation of p27Kip1 and inhibition of epithelial-mesenchymal transition. Pathol Res Pract, 2020, 216(8): 153002. doi: 10.1016/j.prp.2020.153002.
12.	Choi SH, Barker EC, Gerber KJ, et al. Loss of p27Kip1 leads to expansion of CD4⁺ effector memory T cells and accelerates colitis-associated colon cancer in mice with a T cell lineage restricted deletion of Smad4. Oncoimmunology, 2020, 9(1): 1847832. doi: 10.1080/2162402X.2020.1847832.
13.	张永健, 郭学海, 高秀凤, 等. Skp2及p27kip1在原发性胃癌组织的表达及对胃癌细胞增殖、凋亡的影响. 中国实验诊断学, 2023, 27(5): 591-596.
14.	Rampioni Vinciguerra GL, Dall'Acqua A, Segatto I, et al. p27kip1 expression and phosphorylation dictate palbociclib sensitivity in KRAS-mutated colorectal cancer. Cell Death Dis, 2021, 12(10): 951. doi: 10.1038/s41419-021-04241-2.
15.	Wang P, Zhang W, Wang L, et al. RCC2 Interacts with Small GTPase RalA and regulates cell proliferation and motility in gastric cancer. Onco Targets Ther, 2020, 13: 3093-3103.
16.	Nanami T, Hoshino I, Ito M, et al. Prevalence of autoantibodies against Ras-like GTPases, RalA, in patients with gastric cancer. Mol Clin Oncol, 2020, 13(4): 28. doi: 10.3892/mco.2020.2098.
17.	Richardson DS, Spehar JM, Han DT, et al. The RAL enigma: Distinct roles of RALA and RALB in cancer. Cells, 2022, 11(10): 1645. doi: 10.3390/cells11101645.
18.	Zhang BY, Zhang L, Chen YM, et al. Corosolic acid inhibits colorectal cancer cells growth as a novel HER2/HER3 heterodimerization inhibitor. Br J Pharmacol, 2021, 178(6): 1475-1491.
19.	Li J, Wu C, Hu H, et al. Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer. Cancer Cell, 2023, 41(6): 1152-1169.
20.	Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol, 2020, 17(8): 807-821.
21.	Gan C, Li M, Lu Y, et al. SPOCK1 and POSTN are valuable prognostic biomarkers and correlate with tumor immune infiltrates in colorectal cancer. BMC Gastroenterol, 2023, 23(1): 4. doi: 10.1186/s12876-022-02621-2.
22.	史春桃, 程杰, 刘慧, 等. SPOCK1, MMP11与MMP9在结直肠癌中的表达及临床价值. 重庆医学, 2023, 52(1): 102-107.
23.	Liu HX, Cao YY, Qu JY. SPOCK1 promotes the proliferation and migration of colon cancer cells by regulating the NF-κB pathway and inducing EMT. Neoplasma, 2021, 68(4): 702-710.
24.	高秀凤, 张永健, 郭学海, 等. skp2及p27Kip1蛋白与晚期胃癌患者临床预后的关系. 中国老年学杂志, 2023, 43(23): 5667-5670.

1. 黄理宾, 黄秋实, 杨烈. 全球及中国的结直肠癌流行病学特征及防治: 2022《全球癌症统计报告》解读. 中国普外基础与临床杂志, 2024, 31(5): 530-537.
2. 1Ionescu VA, Gheorghe G, Bacalbasa N, et al. Colorectal cancer: From risk factors to oncogenesis. Medicina (Kaunas), 2023, 59(9): 1646. doi: 10.3390/medicina59091646.
3. Oliveres H, Cascante M, Maurel J. Metabolic interventions to enhance immunotherapy and targeted therapy efficacy in advanced colorectal cancer. Curr Opin Chem Biol, 2023 Dec: 77: 102401.
4. Goyal R, Wassie MM, Winter JM, et al. Progress in the field of noninvasive diagnostics for colorectal cancer: a systematic review for the accuracy of blood-based biomarkers for detection of advanced pre-cancerous lesions. Expert Rev Mol Diagn, 2023, 23(12): 1233-1250.
5. Liu M, Xu X, Peng K, et al. Heparanase modulates the prognosis and development of BRAF V600E-mutant colorectal cancer by regulating AKT/p27Kip1/Cyclin E2 pathway. Oncogenesis, 2022, 11(1): 58.
6. Ushigome M, Shimada H, Nabeya Y, et al. Possible predictive significance of serum RalA autoantibodies on relapse-free survival in patients with colorectal cancer. Mol Clin Oncol, 2021, 14(1): 18. doi: 10.3892/mco.2020.2180.
7. Qu YL, Liu XL, Zhao SY, et al. SPOCK1 silencing decreases 5-FU resistance through PRRX1 in colorectal cancer. Pathol Res Pract, 2022, 234: 153895. doi: 10.1016/j.prp.2022.153895.
8. 中华人民共和国卫生和计划生育委员会医政医管局, 中华医学会肿瘤学分会. 中国结直肠癌诊疗规范(2017年版). 中华外科杂志, 2018, 56(4): 241-258.
9. Murphy CC, Zaki TA. Changing epidemiology of colorectal cancer—birth cohort effects and emerging risk factors. Nat Rev Gastroenterol Hepatol, 2024, 21(1): 25-34.
10. Song M, Chan AT, Sun J. Influence of the gut microbiome, diet, and environment on risk of colorectal cancer. Gastroenterology, 2020, 158(2): 322-340.
11. Zhang D, Wu P, Zhang Z, et al. Overexpression of negative regulator of ubiquitin-like proteins 1 (NUB1) inhibits proliferation and invasion of gastric cancer cells through upregulation of p27Kip1 and inhibition of epithelial-mesenchymal transition. Pathol Res Pract, 2020, 216(8): 153002. doi: 10.1016/j.prp.2020.153002.
12. Choi SH, Barker EC, Gerber KJ, et al. Loss of p27Kip1 leads to expansion of CD4⁺ effector memory T cells and accelerates colitis-associated colon cancer in mice with a T cell lineage restricted deletion of Smad4. Oncoimmunology, 2020, 9(1): 1847832. doi: 10.1080/2162402X.2020.1847832.
13. 张永健, 郭学海, 高秀凤, 等. Skp2及p27kip1在原发性胃癌组织的表达及对胃癌细胞增殖、凋亡的影响. 中国实验诊断学, 2023, 27(5): 591-596.
14. Rampioni Vinciguerra GL, Dall'Acqua A, Segatto I, et al. p27kip1 expression and phosphorylation dictate palbociclib sensitivity in KRAS-mutated colorectal cancer. Cell Death Dis, 2021, 12(10): 951. doi: 10.1038/s41419-021-04241-2.
15. Wang P, Zhang W, Wang L, et al. RCC2 Interacts with Small GTPase RalA and regulates cell proliferation and motility in gastric cancer. Onco Targets Ther, 2020, 13: 3093-3103.
16. Nanami T, Hoshino I, Ito M, et al. Prevalence of autoantibodies against Ras-like GTPases, RalA, in patients with gastric cancer. Mol Clin Oncol, 2020, 13(4): 28. doi: 10.3892/mco.2020.2098.
17. Richardson DS, Spehar JM, Han DT, et al. The RAL enigma: Distinct roles of RALA and RALB in cancer. Cells, 2022, 11(10): 1645. doi: 10.3390/cells11101645.
18. Zhang BY, Zhang L, Chen YM, et al. Corosolic acid inhibits colorectal cancer cells growth as a novel HER2/HER3 heterodimerization inhibitor. Br J Pharmacol, 2021, 178(6): 1475-1491.
19. Li J, Wu C, Hu H, et al. Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer. Cancer Cell, 2023, 41(6): 1152-1169.
20. Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol, 2020, 17(8): 807-821.
21. Gan C, Li M, Lu Y, et al. SPOCK1 and POSTN are valuable prognostic biomarkers and correlate with tumor immune infiltrates in colorectal cancer. BMC Gastroenterol, 2023, 23(1): 4. doi: 10.1186/s12876-022-02621-2.
22. 史春桃, 程杰, 刘慧, 等. SPOCK1, MMP11与MMP9在结直肠癌中的表达及临床价值. 重庆医学, 2023, 52(1): 102-107.
23. Liu HX, Cao YY, Qu JY. SPOCK1 promotes the proliferation and migration of colon cancer cells by regulating the NF-κB pathway and inducing EMT. Neoplasma, 2021, 68(4): 702-710.
24. 高秀凤, 张永健, 郭学海, 等. skp2及p27Kip1蛋白与晚期胃癌患者临床预后的关系. 中国老年学杂志, 2023, 43(23): 5667-5670.

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Latest ArticlesExpressions of p27Kip1, RalA, and SPOCK1 in elderly colorectal cancer patients and relation between their expressions and prognosis

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