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Background: While previous studies have indicated variability in distant metastatic potential among different mismatch repair (MMR) states in colorectal cancer (CRC), their findings remain inconclusive, especially considering potential differences across various ethnic backgrounds. Furthermore, the gene regulatory networks and the underlying mechanisms responsible for these variances in metastatic potential across MMR states have yet to be elucidated. Methods: We collected 2058 consecutive primary CRC samples from the South West of China and assessed the expression of MMR proteins (MLH1, MSH2, MSH6, and PMS2) using immunohistochemistry. To explore the inconsistencies between different MMR statuses and recurrence, we performed a meta‐analysis. To delve deeper, we employed Weighted Gene Co‐expression Network Analysis (WGCNA), ClueGo, and iRegulon, pinpointing gene expression networks and key regulatory molecules linked to metastasis and recurrence in CRC. Lastly, both univariate and multivariate Cox regression analyses were applied to determine the impact of core regulatory molecules on metastasis. Results: Of the samples, 8.2% displayed deficient MMR (dMMR), with losses of MLH1 and PSM2 observed in 40.8% and 63.9%, respectively. A unique 24.3% isolated loss of PMS2 without concurrent metastasis was identified, a result that diverges from established literature. Additionally, our meta‐analysis further solidifies the reduced recurrence likelihood in dMMR CRC samples compared to proficient MMR (pMMR). Two gene expression networks tied to distant metastasis and recurrence were identified, with a majority of metastasis‐related genes located on chromosomes 8 and 18. An IRF1 positive feedback loop was discerned in the metastasis‐related network, and IRF1 was identified as a predictive marker for both recurrence‐free and distant metastasis‐free survival across multiple datasets. Conclusion: Geographical and ethnic factors might influence peculiarities in MMR protein loss. Our findings also highlight new gene expression networks and crucial regulatory molecules in CRC metastasis, enhancing our comprehension of the mechanisms driving distant metastasis. [ABSTRACT FROM AUTHOR]

Simple Summary: Statins are crucial for managing lipid disorders by inhibiting HMG-CoA reductase, reducing cholesterol levels, and lowering cardiovascular disease risk. Beyond cholesterol control, they exhibit pleiotropic effects, particularly in cancer. Statins influence key cancer pathways, inhibiting proliferation, angiogenesis, metastasis, and cancer stemness, while inducing oxidative stress, cell cycle arrest, autophagy, and apoptosis. Clinical studies suggest statin use associates with reduced cancer risk, lower-grade tumors at diagnosis, decreased local recurrence, and improved survival. This review aims to summarize the mechanisms underpinning statins' anticancer properties and their clinical implications, highlighting their potential as a valuable tool in cancer prevention and treatment. Statins are an essential medication class in the treatment of lipid diseases because they inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. They reduce cholesterol levels and reduce the risk of cardiovascular disease in both primary and secondary prevention. In addition to their powerful pharmacologic suppression of cholesterol production, statins appear to have pleitropic effects in a wide variety of other diseases by modulating signaling pathways. In recent years, statins have seen a large increase in interest due to their putative anticancer effects. Statins appear to cause upregulation or inhibition in key pathways involved in cancer such as inhibition of proliferation, angiogenesis, and metastasis as well as reducing cancer stemness. Further, statins have been found to induce oxidative stress, cell cycle arrest, autophagy, and apoptosis of cancer cells. Interestingly, clinical studies have shown that statin use is associated with a decreased risk of cancer formation, lower cancer grade at diagnosis, reduction in the risk of local reoccurrence, and increasing survival in patients. Therefore, our objective in the present review is to summarize the findings of the publications on the underlying mechanisms of statins' anticancer effects and their clinical implications. [ABSTRACT FROM AUTHOR]

Objective: Particularly interesting new cysteine-histidine rich protein (PINCH) is an important component of the local adhesion complexes and upregulated in several types of malignancies, and involved in the incidence and development of tumours. PINCH expression is also independently correlated with poorer survival in patients with colorectal cancer. However, there is no study of PINCH in gastric cancer, therefore, the aim of this project was to investigate PINCH expression and its clinicopathological significance in gastric adenocarcinoma. Patients and methods: PINCH expression was immunohistochemically examined in normal gastric mucous (n=30) and gastric adenocarcinoma (n=73), from gastric cancer patients. Results: PINCH expression in the associated-stroma of gastric cancers was heterogeneous, and its positive rate (75%) was higher than that of normal gastric mucosa (43%, X^{2} =9.711, p=0.002). The stronger staining was observed at the invasive edge of tumour when compared to the inner area of tumour. The rate of positive PINCH (88%) in the cases with lymph node metastasis was higher than that (52%) in the cases without metastasis (X^{2}=11.151, p=0.001). PINCH expression was not correlated with patients' gender, age, tumour size, differentiation and invasion depth (p> 0.05). Comclusion: PINCH protein might play an important role in the tumourigenesis and metastasis of gastric adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background: Expression of WRAP53 protein has oncogenic properties and it is up regulated in several types of tumors. Methods: We examined expression of WRAP53 protein in rectal cancers and analyzed its relationship to the response to preoperative radiotherapy and patient survival. The WRAP53 protein was examined by immunohistochemistry in normal mucosa, primary tumors and lymph node metastases from 143 rectal cancer patients participated in a Swedish clinical trial of preoperative radiotherapy. Results: Frequency of WRAP53 protein expression was increased in primary rectal cancer compared to the normal mucosa (p<0.05). In non-radiotherapy group positive WRAP53 in primary tumors (p = 0.03, RR, 3.73, 95% CI, 1.13-11.89) or metastases (p = 0.01, RR, 4.11, 95% CI, 1.25-13.14), was associated with poor prognosis independently of stages and differentiations. In radiotherapy group, positive WRAP53 in the metastasis correlated with better survival (p = 0.04). An interaction analysis showed that the correlations of WRAP53 with the prognostic significance with and without radiotherapy in the metastasis differed (p = 0.01). In the radiotherapy group, expression of WRAP53 in metastases gave a better outcome (p = 0.02, RR, 0.32, 95% CI, 0.13-0.84), and an interaction analysis showed significance between the two groups (p = 0.01). Conclusion: WRAP53 may be a new biomarker used to predict prognosis and to select suitable patients for preoperative radiotherapy. [ABSTRACT FROM AUTHOR]

Background: Expression of the meningioma-associated protein (MAC30) was increased in several types of tumors, including esophageal, gastric and colon tumors, compared to normal tissue. MAC30 expression levels gradually increased from normal colorectal mucosa to primary colorectal cancer and colorectal cancer spreading to the lymph nodes. MAC30 expression was related to survival in patients with colorectal cancer. However, there is no study on MAC30 in oral squamous cell carcinoma (OSCC). Methods: Therefore, MAC30 expression in OSCC was investigated and possible associations of MAC30 expression with clinicopathological variables in OSCC have been analyzed. MAC30 expression was immunohistochemically examined in 20 normal oral mucosa and 43 OSCC specimens. Results: Expression levels of MAC30 in the cytoplasm markedly increased from normal oral epithelial cells to primary OSCC. Strong cytoplasmic staining was significantly higher in primary OSCC compared to normal oral mucosa samples (51 vs. 20%, p = 0.019). Furthermore, MAC30 expression levels in primary tumors of patients with lymph node metastasis exceeded levels in those without metastasis (65 vs. 35%, p = 0.048), and MAC30 expression in poorly differentiated tumors was higher than in well-differentiated ones (90 vs. 39%, p = 0.005). Conclusion: Overexpression of MAC30 in the cytoplasm of OSCC may predict nodal metastasis and poor differentiation. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective. The inhibitory proteins, IκBs, regulate the activity of nuclear factor kappa-beta (NF-κB), which is implicated in tumorigenesis by regulating expression of a variety of genes involved in cellular transformation, proliferation, invasion, angiogenesis and metastasis. Variants in the genes encoding IκBs may be involved in cancer development through the activation of NF-κB. The objective of this study was to investigate the susceptibility of an A to G variation (rs696) in the 3′ UTR of NFKBIA (encoding IκBα) to colorectal cancer (CRC) and the association of this polymorphism with clinicopathologic variables in CRC patients. Material and methods. A case-control study was carried out on a Swedish (155 CRCs, 438 controls) and a Chinese population (199 CRCs, 577 controls). The genotype of NFKBIA was determined by PCR-restriction fragment length polymorphism. Results. The frequency of the AG genotype was increased in the Chinese patients ≥50 years of age compared with the Chinese controls (odds ratio (OR) = 3.06, 95% confidence interval (CI) = 1.55–6.02, p=0.001), even when adjusted for age (OR = 3.20, 95% CI = 1.61–6.38, p=0.001). The GG genotype of NFKBIA was related to a poorer survival rate in the Swedish patients, independent of gender, age, tumour location, Dukes’ stage and differentiation (hazard ratio = 3.10, 95% Cl = 1.28–7.60, p=0.01). Conclusions. Chinese individuals ≥50 years of age carrying the AG genotype of NFKBIA may be at an increased risk of developing CRC, and the GG genotype of NFKBIA may be considered as a prognostic factor for Swedish CRC patients. [ABSTRACT FROM AUTHOR]

Purpose: To investigate p73 expression in normal mucosa, primary tumor, and metastasis in relation to radiotherapy (RT) response and clinicopathologic/biologic variables in rectal cancers.Methods and Materials: p73 was immunohistochemically examined on biopsies (unirradiated, n=102), distant (from the large bowel, n=82), and adjacent (adjacent to primary tumor, n=89) normal mucosa samples, primary tumors (n=131), and lymph node metastasis (n=32) from rectal cancer patients participating in a clinical trial of preoperative RT. Seventy-four patients received surgery alone and 57 received additional RT.Results: Cytoplasmic p73 was increased in the primary tumor compared with the distant or adjacent mucosa (pConclusions: Normal epithelial cells seem more sensitive to RT than tumor cells regarding p73 expression. Patients with p73-negative rectal tumors may have a lower risk of local recurrence after RT. [ABSTRACT FROM AUTHOR]

Purpose: PRL-3 (phosphatase of regenerating liver) is involved in metastasis of colorectal cancer; however, its therapeutic implication in cancer patients has not been studied. We investigated the relationships of PRL expression to radiotherapy (RT) in rectal cancer patients. Methods and Materials: Phosphatase of regenerating liver expression was immunohistochemically examined in distant (n = 36) and adjacent (n = 82) normal mucosa, primary tumor (n = 125), biopsy specimens (n = 96), and lymph node metastasis (n = 30) from rectal cancer patients participating in a clinical trial of preoperative RT. Results: Phosphatase of regenerating liver expression was increased from the distant to adjacent mucosa and to the primary tumor (p < 0.05). PRL was highly expressed at the invasive margin in 28% of the primary tumors and 26% of the metastases. In the RT group, strong PRL expression at the invasive margin was related to distant recurrence (p = 0.006) and poor survival (p = 0.01), but not in the non-RT group. The survival significance remained even after adjusting for Dukes’ stage and differentiation (p = 0.02). Additional multivariate analyses showed that the correlation with prognostic significance of PRL differed between the RT and non-RT groups (p = 0.01). Conclusion: Phosphatase of regenerating liver expression (rather than PRL-3 alone) at the invasive margin predicted resistance to RT and unfavorable survival in rectal cancer patients with preoperative RT. [Copyright &y& Elsevier]