Biomarkers for predicting chemotherapy response are important to treatment of colorectal cancer (CRC) patients. Cryptochrome 2 (CRY2) is a circadian clock protein involved in cell cycle, but the biological consequences of this activity in cancer are poorly understood. We set up biochemical and cell biology analyses to analyze CRY2 expression and chemoresistance. Here we report that CRY2 is overexpressed in chemoresistant CRC samples, and CRY2 overexpression is correlated with poor patient survival. Knockdown CRY2 increased colorectal cancer sensitivity to oxaliplatin in colorectal cancer cell. We also identify FBXW7 as a novel E3 ubiquitin ligase for targeting CRY2 through proteasomal degradation. Mechanistic studies show that CRY2 is regulated by FBXW7, in which FBXW7 binds directly to phosphorylated Thr300 of CRY2. Furthermore, FBXW7 expression leads to degradation of CRY2 through enhancing CRY2 ubiquitination and accelerating CRY2’s turnover rate. High expressed FBXW7 downregulates CRY2 and increases colorectal cancer cells sensitivity to chemotherapy. Low FBXW7 expression is correlated with high CRY2 expression in CRC patient samples. Also, low FBXW7 expression is correlated with poor patient survival. Taken together, our findings indicate that the upregulation of CRY2 caused by downregulation of FBXW7 may be a novel prognostic biomarker and may represent a new therapeutic target in colorectal cancer.
Although abnormal expression of eukaryotic initiation factor 6 (eIF6) has been found in several human solid tumors, the functions and underlying mechanisms of eIF6 in the progression of colorectal cancer (CRC) still needs further elucidation. In the present study, large-scale gene analysis based on Oncomine and The Cancer Genome Atlas (TCGA) database revealed significantly higher baseline expression of eIF6 in colorectal cancer than in normal tissues. Furthermore, our Chinese cohort study revealed that high expression of eIF6 was correlated with aggressive characteristics and poor survival in CRC patients. Functional studies using magnetic nanoparticle extraction indicated that eIF6 was an oncogene in CRC cells. Regarding its mechanism, through Gene ontology (GO) and KEGG pathway analysis based on TCGA RNAseq database, we found that eIF6 can activate multiple AKT-related cancer signaling pathways, such as p-AKT\MMP1\cyclinD1\Bcl2-related signaling, to regulate cell proliferation, invasion, cell cycle and apoptosis in CRC. Collectively, these findings suggested that eIF6 can positively regulate AKT-related cancer signaling and enhance tumorigenicity in CRC, and may serve as a potential prognostic indicator and therapeutic target in CRC.
Background: Serum CEA has been widely used to screen for potential recurrent disease after resection in rectal cancer. However, the influence of baseline CEA on the performance of CEA in recurrence surveillance needs to be investigated. Patients and Methods: This longitudinal cohort study included 484 patients with nonmetastatic rectal cancer from 18,013 patients in a prospectively enrolled institutional database program of colorectal disease. Baseline CEA levels were determined before treatment, and CEA-based follow-up tests and examinations were applied in the surveillance after treatment. Results: A total of 62.6% (62/99) overall, 53.5% (23/43) local, and 64.9% (50/77) distant recurrences were seen in patients who had similar CEA levels with their baseline statuses. The sensitivity of elevated CEA levels during surveillance for overall recurrence was significantly lower in patients with negative baseline CEA than in those with elevated baseline CEA levels (41.3% vs 69.4%; P =.007). Moreover, similar results were observed in the surveillance for local (50% vs 61.5%; P =.048) and distant (39.6% vs 72.4%; P =.005) recurrences between these 2 patient groups. However, CEA had comparable and excellent specificity during surveillance for recurrent disease in these groups. The addition of CA19-9 to the CEA assay significantly improved the sensitivity in recurrence surveillance for patients with negative baseline CEA (49.2% vs 41.3%; P =.037). Finally, we identified a subgroup of CEA-turn recurrences characterized by negative CEA at baseline, elevated CEA at recurrence, and worse survival outcomes after recurrence (hazard ratio, 1.88; 95% CI, 1.07–3.30; P =.026). Conclusions: In patients with rectal cancer with negative baseline CEA, serum CEA had insufficient sensitivity in recurrence surveillance after treatment, and additional surveillance may improve oncologic outcomes. Baseline CEA should be considered before CEA-based surveillance can be applied in the follow-up trials.
Abstract. Mitogen-activated protein kinase kinase kinase 2 (MEKK2) is an important upstream mediator of the extracellular signal-regulated kinase 5 signaling cascade that is essential for a number of cellular functions, including mitogenesis, differentiation and oncogenic transformation. Using western blotting to examine MEKK2 expression in 16 cases of primary colorectal cancer (CRC) lesions with paired normal mucosa, it was identified that MEKK2 is highly expressed in CRC lesions compared with that of the normal mucosa. Immunohistochemistry of 24 normal mucosa, 24 adenoma and 96 adenocarcinoma colorectal specimens indicated that the expression of MEKK2 was significantly increased in the adenoma and carcinoma specimens compared with that of the normal mucosa cases (P<0.0001 for both). However, no significant differences were detected in MEKK2 expression between the carcinoma and adenoma specimens (P=0.85). Similarly, no correlations were identified between MEKK2 expression and clinicopathological features, including gender, age, body mass index, histological differentiation, depth of invasion, lymph node metastasis, UICC stage and K-ras mutations (P>0.05). The present study demonstrated that MEKK2 functions as a promotive factor in CRC. IntroductionColorectal cancer (CRC) is the second and third most common type of malignancy in females and males worldwide, respectively (1). In the majority of Asian countries, CRC morbidity has increased rapidly throughout previous decades, and follows a stepwise progression from normal tissue to a premalignant phase to the invasive carcinoma. This process is known as the adenoma-carcinoma sequence. Recently, a number of studies have suggested that the accumulation of multiple gene mutations in key signaling pathways correlates with the multiple steps of colorectal carcinogenesis (2,3). Therefore, it is essential to identify significant molecular biomarkers in these pathways for the prevention and treatment of CRC.Mitogen-activated protein kinase kinase kinase 2 (MEKK2) is a Ser/Thr protein kinase expressed in multiple tissues that belongs to the MEKK/STE11 subgroup of the MAP3K family (4,5). Specifically, MEKK2 is a member of the extracellular signal-regulated kinase 5 (ERK5) signaling cascade that has been previously identified in all four mitogen-activated protein kinase (MAPK) pathways, including MEKK2/3, MEK5 and ERK5 at the MAP3K, MAPKK and MAPK tiers, respectively (6). The ERK5 signaling cascade is essential for the control of cellular proliferation (7) and is likely to be targeted during cell cycle progression (8,9) and tumorigenesis (10,11). In addition, the ERK5 cascade is involved in the management of cell differentiation (12,13), migration (14,15), neuronal survival rate (16), embryonic angiogenesis (17) and additional cellular functions (18-21).MEKK2 has been shown to mediate epidermal growth factor and fibroblast growth factor 2 receptor signals (22,23) which have been previously identified to be involved in the development of various types of cancer (24,25). There...
Background The incidence of colorectal cancer is increasing among young adults and more rectal cancers are reported. This study aimed to identify the clinical features specific for early‐onset rectal cancer and provide insights on cancer management. Methods Early‐onset (<50 years) and late‐onset (≥50 years) rectal cancer patients from a referral tertiary care center (SYSU cohort) and Surveillance Epidemiology and End Results database (SEER cohort) were included to perform a comprehensive comparison on clinical information. Results A total of 552 and 80,341 patients with stages I–III rectal cancer were included in the SYSU and SEER cohorts, respectively. In the SYSU cohort, early‐onset diseases had significantly higher prevalence of family history of cancer and history of HBV infection and lower incidence of comorbidities ( p < 0.05). In addition, early‐onset patients presented more frequently with advanced node stage (N2 stage: 16.9 vs. 9.3%, p = 0.017) and high‐risk features, including mucinous or signet cell carcinomas (21.8 vs. 12.9%, p = 0.014), poorly differentiated tumors (28.8 vs. 15.4%, p = 0.002), and perineural invasion (14.5 vs. 7.9%, p = 0.027) compared with late‐onset patients. However, early‐onset patients received more neoadjuvant (18.5 vs. 11.2%, p = 0.032) and adjuvant treatments (71.0 vs. 45.8%, p < 0.001), and they had better overall survival in both SYSU (HR 0.57, 95% CI: 0.34–0.95; p = 0.029) and SEER (HR 0.38, 95% CI: 0.37–0.40; p < 0.001) cohorts. Conclusion Early‐onset rectal cancers are distinct from late‐onset cases in clinicopathological features, treatment modalities, and outcomes. The clinical trials and studies that are specific for young populations are needed to develop optimal strategies for cancer screening, treatment, and surveillance.
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