Expression of FIBCD1 by intestinal epithelial cells alleviates inflammation-driven tumorigenesis in a mouse model of colorectal cancer.

Background: Colorectal cancer (CRC) ranks as the third most prevalent cancer globally, highlighting the pressing need to address its development. Inflammation plays a crucial role in augmenting the risk of CRC and actively contributes to all stages of tumorigenesis. Consequently, targeting early inflammatory responses in the intestinal tract to restore homeostasis holds significant potential for preventing and treating CRC. Fibrinogen C domain-containing 1 (FIBCD1), a chitin-binding transmembrane protein predominantly found on human intestinal epithelial cells (IECs), has garnered attention in previous research for its ability to effectively suppress inflammatory responses and promote tissue homeostasis at mucosal barriers. Methods: In this study, we investigated the role of FIBCD1 in CRC development using transgenic mice that mimic human expression of FIBCD1 at the intestinal mucosal barrier. To model aspects of CRC, we employed the azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model. Additionally, we examined the expression pattern of FIBCD1 in surgical specimens obtained from human CRC patients by immunohistochemical methods. By accessing public data repositories, we further evaluated FIBCD1 expression in colon adenocarcinoma and explored survival outcomes associated with FIBCD1 expression. Results: Here, we demonstrate that FIBCD1 substantially impacts CRC development by significantly reducing intestinal inflammation and suppressing colorectal tumorigenesis in mice. Furthermore, we identify a soluble variant of FIBCD1 that is significantly increased in feces during acute inflammation. Finally, we demonstrate increased expression of FIBCD1 by immunohistochemistry in human CRC specimens at more developed tumor stages. These results are further supported by bioinformatic analyses of publicly available repositories, indicating increased FIBCD1 expression in tumor tissues, where higher expression is associated with unfavorable prognosis. Conclusion: Collectively, these findings suggest that FIBCD1 influences early inflammatory responses in the AOM/DSS model, leading to a reduction in tumor size and burden. The increased expression of FIBCD1 in human CRC samples raises intriguing questions regarding its role in CRC, positioning it as a compelling candidate and novel molecular target for future research.

Suppression of Nanog inhibited cell migration and increased the sensitivity of colorectal cancer cells to 5-fluorouracil.

Nanog is a major transcription factor related to cellular multipotency that plays important roles in the development of tumor cells, drug resistance, migration, and stemness; indicating its great potential as a therapeutic target for various malignancies including colorectal cancer (CRC). Therefore, this study was aimed to evaluate the Nanog suppression effect using small interference RNA (siRNA) combined with 5-fluorouracil (5-FU) on CRC cells. Nanog-overexpressing SW-480 cells were transfected with Nanog si-RNA and treated with 5-FU, in combination or separately. Subsequently, it was observed that Nanog expression was significantly reduced after transfection of SW-480 cells using Nanog siRNA in mRNA and protein levels. Furthermore, Nanog knockdown significantly increased CRC cell sensitivity to 5-FU drug via modulating Bax and Bcl-2 mRNA expression. Also, Nanog knockdown and 5-FU treatment cooperatively decreased the migration and self-renewal ability of SW-480 cells by regulating the expression of relevant genes. Moreover, combination therapy led to cell cycle arrest at the sub-G1 phase in CRC cells. In conclusion, our results indicated that Nanog may play an important role in the drug sensitivity, migration, and self-renewal of CRC cells; suggesting Nanog as a promising target in combination with 5-FU for the development of new therapeutic approaches for CRC.

Regulation of immune responses through CD39 and CD73 in cancer: Novel checkpoints.

The immunosuppressive tumor microenvironment has been implicated in attenuating anti-tumoral immune responses and tumor growth in various cancers. Inhibitory immune checkpoints have been introduced as the primary culprits for developing the immunosuppressive tumor microenvironment. Therefore, a better understanding of the cross-talk between inhibitory immune checkpoints in the tumor microenvironment can pave the way for introducing novel approaches for treating affected patients. Growing evidence indicates that CD39 and CD73, as novel checkpoints, can transform adenosine triphosphate (ATP)-mediated pro-inflammatory tumor microenvironment into an adenosine-mediated immunosuppressive one via the purinergic signaling pathway. Indeed, enzymatic processes of CD39 and CD73 have crucial roles in adjusting the extent, intensity, and chemical properties of purinergic signals. This study aims to review the biological function of CD39 and CD73 and shed light on their significance in regulating anti-tumoral immune responses in various cancers.

Immune checkpoints in tumor microenvironment and their relevance to the development of cancer stem cells.

Cancer is the second cause of mortality in the world after cardiovascular disease. Various studies attribute the emergence of therapeutic resistance in tumors to the presence of cancer stem cells or cancer-initiating cells (CSC/CIC). These relatively rare cells because of their typical stemness features, are responsible for tumor cell progression and recurrence. Moreover, CSCs have immunomodulatory capabilities and through orchestrating, some immunological profiles can stay safe from host anticancer immunity, and provide immunotherapy resistance in cancer patients. Many studies have shown that CSCs by producing immune system inhibitory factors and interacting with immune checkpoint molecules like CD47, PDL-1, CTLA4, Tim3, and LAG3, are able to communicate with tumor microenvironment (TME) components and protect cancer cells from immune clearance. In this review, we summarize the CSCs immunological mechanisms and comprehensively discuss interactions between these cells and factors that are present in the TME to repress immune system responses and enhance tumor survival. Therefore, it seems that further studies on this topic will open new doors to improve the therapeutic approaches of malignant cancers.

Immunotherapeutic effects of chitin in comparison with chitosan against Leishmania major infection.

Chitin and chitosan microparticles (MPs) are important immune system stimulators. The aim of this study was to evaluate the protective effects of these compounds in comparison with each other against Leishmania infection in BALB/c mice infected with Leishmania major (L. major). Female BALB/c mice were injected subcutaneously with 2×10(5) promastigotes. Chitin and/or chitosan MPs (<40 µm) were subcutaneously injected in the BALB/c mice with two-day intervals until two weeks. Mice in all groups were sacrificed at 12 weeks post-infection. Enumeration of viable parasites was performed using limiting dilution assay. Furthermore, the animals (5 mice/group) were sacrificed two weeks post-infection. The lymph node cells were isolated and the effects of the chitinous MPs on the proliferation and production of cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) were determined. The mean sizes of lesions were significantly smaller in chitin (0.6±0.12 mm) and chitosan treated groups (1.2±0.8 mm) than in the control group (6.2±1.7 mm) (P<0.05). The parasite load in the lymph nodes of the treated mice was significantly lower than that in the lymph nodes of controls (1.31×10(6) vs 8.24×10(7) parasite/lymph node [P=0.032] and 7.49×10(6) vs 8.24×10(7) parasite/lymph node [P=0.05] for chitin and chitosan MPs treatment, respectively). We found that chitinous MPs induced cell proliferation and that chitin but not chitosan increased TNF-α and IL-10 production. Chitin appears that it has more effect than chitosan against leishmaniasis. The current study revealed that chitinous MPs had significant activity against L. major and could be considered as new therapeutic modality in leishmaniasis.

BACH1 silencing by siRNA inhibits migration of HT-29 colon cancer cells through reduction of metastasis-related genes.

BACKGROUND: Metastasis to distant organs is a hallmark of many tumor cells. BACH1 (BTB and CNC homology 1) is a transcriptional factor which promotes the migration and invasion of breast cancer cells. BACH1 expression and its target genes are intimately associated with the metastasis possibility of clinical samples, and BACH1 reduction leads to meaningful depletion in metastasis. The evaluation of BACH1 role in colon cancer remains elusive. This study seeks to further investigate the role of BACH1 in colon cancer cells. METHODS: Quantitative RT-PCR (qRT-PCR) was used to detect BACH1 expression and other related metastatic genes following siRNA knockdown in colon cancer HT-29 cells. And the protein level assessed by Western blot. MTT assay was to measure the changed cell viability after BACH1 siRNA transfection. Scratch-wound motility assays measured capacity of tumor cell migration of HT-29 cells after BACH1 silencing. RESULTS: The inhibitory effect of BACH1 was performed by siRNA knockdown using highly metastatic HT-29 colon cell lines. Quantitative RT-PCR and Western blot analysis revealed that the expression levels of BACH1 mRNA and protein in HT29 cells were significantly suppressed after transfection. Conversely, the BACH1 expression increased migration. Also the CXCR4 and MMP1 expression levels decreased following BACH1 knockdown in HT-29 cells. CONCLUSION: Our results indicated that BACH1 down-regulation in HT29 CRC cells had no effect on cell growth but did inhibit cell migration by decreasing metastasis-related genes expression. Collectively, these results suggest that BACH1 may function as an oncogenic driver in colon cancer and may represent as a potential target of gene therapy for CRC treatment.