Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis of CRC is a testament to the dysregulation of these signaling cascades, which culminates in the malignant transformation of colonic epithelium. This review aims to dissect the foundational signaling mechanisms implicated in CRC, to elucidate the generalized principles underpinning neoplastic evolution and progression. We discuss the molecular hallmarks of CRC, including the genomic, epigenomic and microbial features of CRC to highlight the role of signal transduction in the orchestration of the tumorigenic process. Concurrently, we review the advent of targeted and immune therapies in CRC, assessing their impact on the current clinical landscape. The development of these therapies has been informed by a deepening understanding of oncogenic signaling, leading to the identification of key nodes within these networks that can be exploited pharmacologically. Furthermore, we explore the potential of integrating AI to enhance the precision of therapeutic targeting and patient stratification, emphasizing their role in personalized medicine. In summary, our review captures the dynamic interplay between aberrant signaling in CRC pathogenesis and the concerted efforts to counteract these changes through targeted therapeutic strategies, ultimately aiming to pave the way for improved prognosis and personalized treatment modalities in colorectal cancer.

CXCR4 knockdown enhances sensitivity of paclitaxel via the PI3K/Akt/mTOR pathway in ovarian carcinoma.

Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy. EOC control remains difficult, and EOC patients show poor prognosis regarding metastasis and chemotherapy resistance. The aim of this study was to estimate the effect of CXCR4 knockdown-mediated reduction of cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) stemness and enhancement of chemotherapy sensitivity in EOC. Mechanisms contributing to these effects were also explored. Our data showed distinct contribution of CXCR4 overexpression by dependent PI3K/Akt/mTOR signaling pathway in EOC development. CXCR4 knockdown resulted in a reduction in CSCs and EMT formation and enhancement of chemotherapy sensitivity in tumor cells, which was further advanced by blocking CXCR4-PI3K/Akt/mTOR signaling. This study also documented the critical role of silencing CXCR4 in sensitizing ovarian CSCs to chemotherapy. Thus, targeting CXCR4 to suppress EOC progression, specifically in combination with paclitaxel (PTX) treatment, may have clinical application value.

Inhibition of APE1 Expression Enhances the Antitumor Activity of Olaparib in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that is prone to recurrence and metastasis. Because of the lack of expression of estrogen receptor (ER) and progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) in TNBC, treatment methods are greatly limited. In this study, the proliferation inhibition and apoptosis-inducing effects of PARP1 inhibitors in TNBC breast cancer cells and in vivo xenograft animal models were examined to investigate the molecular role of APE1 in PARP1-targeted therapy. In TNBC patients, the expression of APE1 and PARP1 were positively correlated, and high expression of APE1 and PARP1 was associated with poor survival of TNBC. Our results indicated that knockdown APE1 could increase the sensitivity of olaparib in the treatment of TNBC. In conclusion, the results of this study will not only clarify the molecular role of APE1 in PARP1-targeted therapy for TNBC but also provide a theoretical basis for the future clinical application of targeting APE1 and PARP1 in the treatment of refractory TNBC.

PD-L1P146R is prognostic and a negative predictor of response to immunotherapy in gastric cancer.

Cancer cells evade immune detection via programmed cell death 1/programmed cell death-ligand 1 (PD-1/PD-L1) interactions that inactivate T cells. PD-1/PD-L1 blockade has become an important therapy in the anti-cancer armamentarium. However, some patients do not benefit from PD-1/PD-L1 blockade despite expressing PD-L1. Here, we screened 101 gastric cancer (GC) patients at diagnosis and 141 healthy control subjects and reported one such subpopulation of GC patients with rs17718883 polymorphism in PD-L1, resulting in a nonsense P146R mutation. We detected rs17718883 in 44% of healthy control subjects, and rs17718883 was associated with a low susceptibility to GC and better prognosis in GC patients. Structural analysis suggests that the mutation weakens the PD-1:PD-L1 interaction. This was supported by co-culture experiments of T cells, with GC cells showing that the P146R substitution results in interferon (IFN)-γ secretion by T cells and enables T cells to suppress GC cell growth. Similar results with animal gastric tumor models were obtained in vivo. PD-1 monoclonal antibody treatment did not enhance the inhibitory effect of T cells on GC cells expressing PD-L1P146Rin vitro or in vivo. This study suggests that rs17718883 is common and may be used as a biomarker for exclusion from PD-1/PD-L1 blockade therapy.

Proliferation and tenogenic differentiation of bone marrow mesenchymal stem cells in a porous collagen sponge scaffold.

BACKGROUND: Collagen is one of the most commonly used natural biomaterials for tendon tissue engineering. One of the possible practical ways to further enhance tendon repair is to combine a porous collagen sponge scaffold with a suitable growth factor or cytokine that has an inherent ability to promote the recruitment, proliferation, and tenogenic differentiation of cells. However, there is an incomplete understanding of which growth factors are sufficient and optimal for the tenogenic differentiation of rat bone marrow mesenchymal stem cells (BMSCs) in a collagen sponge-based 3D culture system. AIM: To identify one or more ideal growth factors that benefit the proliferation and tenogenic differentiation of rat BMSCs in a porous collagen sponge scaffold. METHODS: We constructed a 3D culture system based on a type I collagen sponge scaffold. The surface topography of the collagen sponge scaffold was observed by scanning electron microscopy. Primary BMSCs were isolated from Sprague-Dawley rats. Cell survival on the surfaces of the scaffolds with different growth factors was assessed by live/dead assay and CCK-8 assay. The mRNA and protein expression levels were confirmed by quantitative real-time polymerase chain reaction and Western blot, respectively. The deposited collagen was assessed by Sirius Red staining. RESULTS: Transforming growth factor ß1 (TGF-ß1) showed great promise in the tenogenic differentiation of BMSCs compared to growth differentiation factor 7 (GDF-7) and insulin-like growth factor 1 (IGF-1) in both the 2D and 3D cultures, and the 3D culture enhanced the differentiation of BMSCs into tenocytes well beyond the level of induction in the 2D culture after TGF-ß1 treatment. In the 2D culture, the proliferation of the BMSCs showed no significant changes compared to the control group after TGF-ß1, IGF-1, or GDF-7 treatment. However, TGF-ß1 and GDF-7 could increase the cell proliferation in the 3D culture. Strangely, we also found more dead cells in the BMSC-collagen sponge constructs that were treated with TGF-ß1. Moreover, TGF-ß1 promoted more collagen deposition in both the 2D and 3D cultures. CONCLUSION: Collagen sponge-based 3D culture with TGF-ß1 enhances the responsiveness of the proliferation and tenogenic differentiation of rat BMSCs.

The transcription factor PBX3 promotes tumor cell growth through transcriptional suppression of the tumor suppressor p53.

Pre-B-cell leukemia transcription factor 3 (PBX3) is a member of the PBX family and contains a highly conserved homologous domain. PBX3 is involved in the progression of gastric cancer, colorectal cancer, and prostate cancer; however, the detailed mechanism by which it promotes tumor growth remains to be elucidated. Here, we found that PBX3 silencing induces the expression of the cell cycle regulator p21, leading to an increase in colorectal cancer (CRC) cell apoptosis as well as suppression of proliferation and colony formation. Furthermore, we found that PBX3 is highly expressed in clinical CRC patients, in whom p21 expression is aberrantly low. We found that the regulation of p21 transcription by PBX3 occurs through the upstream regulator of p21, the tumor suppressor p53, as PBX3 binds to the p53 promoter and suppresses its transcriptional activity. Finally, we revealed that PBX3 regulates tumor growth through regulation of the p53/p21 axis. Taken together, our results not only describe a novel mechanism regarding PBX3-mediated regulation of tumor growth but also provide new insights into the regulatory mechanism of the tumor suppressor p53.

Stiffer Matrix Accelerates Migration of Hepatocellular Carcinoma Cells through Enhanced Aerobic Glycolysis Via the MAPK-YAP Signaling.

Increased extracellular matrix (ECM) stiffness and metabolic reprogramming of cancer cells are two fundamental mediators of tumor progression, including hepatocellular carcinoma (HCC). Yet, the correlation between ECM stiffness and excessive aerobic glycolysis in promoting the development of HCC remains unknown. Here, we demonstrated that stiffer ECM promotes HCC cell migration depending on their accelerated aerobic glycolysis. Our results also indicated that stiffer ECM-induced YAP activation plays a major role in promoting aerobic glycolysis of HCC cells. Moreover, we showed that JNK and p38 MAPK signaling are critical for mediating YAP activation in HCC cells. Together, our findings established that the MAPK-YAP signaling cascade that act as a mechanotransduction pathway is essential for promoting HCC cell aerobic glycolysis and migration in response to ECM stiffness.

Liver cancer stem cell markers: Progression and therapeutic implications.

Cancer stem cells (CSCs) are a small subpopulation in cancer, have been proposed to be cancer-initiating cells, and have been shown to be responsible for chemotherapy resistance and cancer recurrence. The identification of CSC subpopulations inside a tumor presents a new understanding of cancer development because it implies that tumors can only be eradicated by targeting CSCs. Although advances in liver cancer detection and treatment have increased the possibility of curing the disease at early stages, unfortunately, most patients will relapse and succumb to their disease. Strategies aimed at efficiently targeting liver CSCs are becoming important for monitoring the progress of liver cancer therapy and for evaluating new therapeutic approaches. Herein, we provide a critical discussion of biological markers described in the literature regarding liver cancer stem cells and the potential of these markers to serve as therapeutic targets.

Inhibition of hepatitis B virus replication by small interference RNA induces expression of MICA in HepG2.2.15 cells.

Hepatitis B virus (HBV) replicates in most tumor tissues of patients with HBV-associated hepatocellular carcinoma (HCC). In the present study, we have shown that the expression of HBV in the HCC cell lines, HepG2 and Huh7, down-regulated the expression of MHC class I-related molecule A (MICA), a ligand of the NKG2D receptor. Inhibition of HBV expression by small interference RNAs (siRNAs) in HepG2.2.15, a cell line that constitutively expresses HBV, induced up-regulation of MICA. The up-regulation of MICA increased the lysis of HepG2.2.15 cells by NK cells. Our results suggest that HBV compromises the innate immune system in HCC patients and that inhibition of HBV replication by siRNAs may enhance the antitumor immune response.

Induction of MHC class I-related chain B (MICB) by 5-aza-2'-deoxycytidine.

5-Aza-2'-deoxycytidine (5-aza-dC), a DNA methyltransferase inhibitor, exerts antitumor activity through induction of cell cycle arrest, apoptosis and DNA damage. In this study, we showed that MHC class I-related chain B (MICB), a ligand of the NKG2D receptor expressed by natural killer cells and activated CD8(+) T cells, was upregulated following 5-aza-dC treatment. The upregulation of MICB was accompanied by promoter DNA demethylation and DNA damage. Furthermore, the upregulation of MICB was partially prevented by pharmacological or genetic inhibition of ataxia telangiectasia mutated (ATM) kinase. Our results suggest that promoter DNA demethylation, in combination with DNA damage, contribute to the upregulation of MICB induced by 5-aza-dC.

Adhesion of different cell cycle human hepatoma cells to endothelial cells and roles of integrin beta1.

AIM: To investigate the adhesive mechanical properties of different cell cycle human hepatoma cells (SMMC-7721) to human umbilical vein endothelial cells (ECV-304), expression of adhesive molecule integrinbeta1 in SMMC-7721 cells and its contribution to this adhesive course. METHODS: Adhesive force of SMMC-7721 cells to endothelial cells was measured using micropipette aspiration technique. Synchronous G1 and S phase SMMC-7721 cells were achieved by thymine-2-deoxyriboside and colchicines sequential blockage method and double thymine-2-deoxyriboside blockage method, respectively. Synchronous rates of SMMC-7721 cells and expression of integrinbeta1 in SMMC-7721 cells were detected by flow cytometer. RESULTS: The percentage of cell cycle phases of general SMMC-7721 cells was 11.01% in G2/M phases, 53.51% in G0/G1 phase, and 35.48% in S phase. The synchronous rates of G1 and S phase SMMC-7721 cells amounted to 74.09% and 98.29%, respectively. The adhesive force of SMMC-7721 cells to endothelial cells changed with the variations of adhesive time and presented behavior characteristics of adhesion and de-adhesion. S phase SMMC-7721 cells had higher adhesive forces than G1 phase cells ((307.65+/-92.10) x 10(-10) N vs (195.42+/-60.72) x 10(-10) N, P<0.01). The expressive fluorescent intensity of integrinbeta(1) in G(1) phase SMMC-7721 cells was depressed more significantly than the values of S phase and general SMMC-7721 cells. The contribution of adhesive integrinbeta1 was about 53% in this adhesive course. CONCLUSION: SMMC-7721 cells can be synchronized preferably in G1 and S phases with thymine-2-deoxyriboside and colchicines. The adhesive molecule integrinbeta1 expresses a high level in SMMC-7721 cells and shows differences in various cell cycles, suggesting integrin beta1 plays an important role in adhesion to endothelial cells. The change of adhesive forces in different cell cycle SMMC-7721 cells indicates that S phase cells play predominant roles possibly while they interact with endothelial cells.