Horner syndrome immediately after deep dissection of upper thyroid pole: a case report and review of the literature.

Objectives: Horner syndrome (HS) is a rare complication of thyroid surgery. However, the relationship between the occurrence of HS and thyroid upper pole injury is still not completely clear, and there are only few reports. Case presentation: A 24-year-old female underwent endoscopic thyroidectomy for thyroid papillary carcinoma. The intraoperative examination found that the upper pole of the thyroid was bleeding. During hemostasis, the ultrasonic knife consciously peeled too deep and stopped. The patient developed HS immediately after operation. We analyzed the association between deep dissection of the upper thyroid pole and an increase in the HS incidence rate through literature searches and anatomical relationships. Conclusions: Our case report discussed the potential relationship between the degree of thyroid upper pole dissection and the occurrence of HS in routine thyroid surgery, and provided a warning for the degree of thyroid upper pole dissection in the clinic to avoid HS.

PGR-KITLG signaling drives a tumor-mast cell regulatory feedback to modulate apoptosis of breast cancer cells.

The immune microenvironment constructed by tumor-infiltrating immune cells and the molecular phenotype defined by hormone receptors (HRs) have been implicated as decisive factors in the regulation of breast cancer (BC) progression. Here, we found that the infiltration of mast cells (MCs) informed impaired prognoses in HR(+) BC but predicted improved prognoses in HR(-) BC. However, molecular features of MCs in different BC remain unclear. We next discovered that HR(-) BC cells were prone to apoptosis under the stimulation of MCs, whereas HR(+) BC cells exerted anti-apoptotic effects. Mechanistically, in HR(+) BC, the KIT ligand (KITLG), a major mast cell growth factor in recruiting and activating MCs, could be transcriptionally upregulated by the progesterone receptor (PGR), and elevate the production of MC-derived granulin (GRN). GRN attenuates TNFα-induced apoptosis in BC cells by competitively binding to TNFR1. Furthermore, disruption of PGR-KITLG signaling by knocking down PGR or using the specific KITLG-cKIT inhibitor iSCK03 potently enhanced the sensitivity of HR(+) BC cells to MC-induced apoptosis and exerted anti-tumor activity. Collectively, these results demonstrate that PGR-KITLG signaling in BC cells preferentially induces GRN expression in MCs to exert anti-apoptotic effects, with potential value in developing precision medicine approaches for diagnosis and treatment.

IR-780 Dye-based Targeting of Cancer-associated Fibroblasts Improves Cancer Immunotherapy by Increasing Intra-tumoral T Lymphocytes Infiltration.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) against programmed death (PD)-1/PD-L1 pathway immunotherapy have been demonstrated to be effective in only a subset of patients with cancer, while the rest may exhibit low response or may develop drug resistance after initially responding. Previous studies have indicated that extensive collagen-rich stroma secreted by cancer-associated fibroblasts (CAFs) within the tumor microenvironment is one of the key obstructions of the immunotherapy for some tumors by decreasing the infiltrating cytotoxic T cells. However, there is still a lack of effective therapeutic strategies to control the extracellular matrix by targeting CAFs. METHODS: The enhanced uptake of IR-780 by CAFs was assessed by using in vivo or ex vivo nearinfrared fluorescence imaging, confocal NIR fluorescent imaging, and CAFs isolation testing. The fibrotic phenotype down-regulation effects and in vitro CAFs killing effect of IR-780 were tested by qPCR, western blot, and flow cytometry. The in vivo therapeutic enhancement of anti-PD-L1 by IR-780 was evaluated on EMT6 and MC38 subcutaneous xenograft mice models. RESULTS: IR-780 has been demonstrated to be preferentially taken up by CAFs and accumulate in the mitochondria. Further results identified low-dose IR-780 to downregulate the fibrotic phenotype, while high-dose IR-780 could directly kill both CAFs and EMT6 cells in vitro. Moreover, IR-780 significantly inhibited extracellular matrix (ECM) protein deposition in the peri-tumoral stroma on subcutaneous EMT6 and MC38 xenografts, which increased the proportion of tumor-infiltrating lymphocytes (TILs) in the deep tumor and further promoted anti-PD-L1 therapeutic efficacy. CONCLUSION: This work provides a unique strategy for the inhibition of ECM protein deposition in the tumor microenvironment by targeted regulating of CAFs, which destroys the T cell barrier and further promotes tumor response to PD-L1 monoclonal antibody. IR-780 has been proposed as a potential therapeutic small-molecule adjuvant to promote the effect of immunotherapy.

Released dsDNA-triggered inflammasomes serve as intestinal radioprotective targets.

Objectives: Intestinal mucositis is the major side effect during abdominal or pelvic radiotherapy, but the underlying immunogen remains to be further characterised and few radioprotective agents are available. This study investigated the role of dsDNA-triggered inflammasomes in intestinal mucositis during radiotherapy. Methods: Pro-inflammatory cytokines were detected by ELISA. Radiation-induced intestinal injury in mice was analyzed by means of survival curves, body weight, HE staining of intestines, and intestinal barrier integrity. Western blot, immunofluorescence staining, co-immunoprecipitation assay and flow cytometry were used to investigate the regulatory role of dsDNA on inflammasomes. Results: Here, we show that a high level of IL-1ß and IL-18 is associated with diarrhoea in colorectal cancer (CRC) patients during radiotherapy, which accounts for intestinal radiotoxicity. Subsequently, we found that the dose-dependently released dsDNA from the intestinal epithelial cells (IECs) serves as the potential immunogenic molecule for radiation-induced intestinal mucositis. Our results further indicate that the released dsDNA transfers into the macrophages in an HMGB1/RAGE-dependent manner and then triggers absent in melanoma 2 (AIM2) inflammasome activation and the IL-1ß and IL-18 secretion. Finally, we show that the FDA-approved disulfiram (DSF), a newly identified inflammasome inhibitor, could mitigate intestinal radiotoxicity by controlling inflammasome. Conclusion: These findings indicate that the extracellular self-dsDNA released from the irradiated IECs is a potential immunogen to stimulate immune cells and trigger the subsequent intestinal mucositis, while blunting the dsDNA-triggered inflammasome in macrophages may represent an exciting therapeutic strategy for side effects control during abdominal radiotherapy.

Characteristics of recurrence, predictors for relapse and prognosis of rapid relapse triple-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) patients who recur at different times are associated with distinct biological characteristics and prognoses. Research on rapid-relapse TNBC (RR-TNBC) is sparse. In this study, we aimed to describe the characteristics of recurrence, predictors for relapse, and prognosis in rrTNBC patients. Methods: Clinicopathological data of 1584 TNBC patients from 2014 to 2016 were retrospectively reviewed. The characteristics of recurrence were compared between patients with RR-TNBC and slow relapse TNBC(SR-TNBC). All TNBC patients were randomly divided into a training set and a validation set to find predictors for rapid relapse. The multivariate logistic regression model was used to analyze the data of the training set. C-index and brier score analysis for predicting rapid relapse in the validation set was used to evaluate the discrimination and accuracy of the multivariate logistic model. Prognostic measurements were analyzed in all TNBC patients. Results: Compared with SR-TNBC patients, RR-TNBC patients tended to have a higher T staging, N staging, TNM staging, and low expression of stromal tumor-infiltrating lymphocytes (sTILs). The recurring characteristics were prone to appear as distant metastasis at the first relapse. The first metastatic site was apt to visceral metastasis and less likely to have chest wall or regional lymph node metastasis. Six predictors (postmenopausal status, metaplastic breast cancer,≥pT3 staging,≥pN1 staging, sTIL intermediate/high expression, and Her2 [1+]) were used to construct the predictive model of rapid relapse in TNBC patients. The C-index and brier score in the validation set was 0.861 and 0.095, respectively. This suggested that the predictive model had high discrimination and accuracy. The prognostic data for all TNBC patients showed that RR-TNBC patients had the worst prognosis, followed by SR-TNBC patients. Conclusion: RR-TNBC patients were associated with unique biological characteristics and worse outcomes compared to non-RR-TNBC patients.

Circ-C16orf62 Regulates Oxidized low-density Lipoprotein-induced Apoptosis, Inflammation, Oxidative Stress and Cholesterol Accumulation of Macrophages via Mediating RAB22A Expression by Targeting miR-377.

Atherosclerosis (AS) is one of the most common and important vascular diseases. It is believed that the abnormal expression of circular RNAs (circRNAs) plays an important role in AS. Hence, we investigate the function and mechanism of circ-C16orf62 in AS development.In this study, oxidized low-density lipoprotein (ox-LDL)-treated human macrophages (THP-1) were used as pathological conditions of AS in vitro. The expression of circ-C16orf62, miR-377 and Ras-related protein (RAB22A) mRNA was detected by real-time quantitative polymerase chain reaction (RT-qPCR) or western blot. Cell viability or cell apoptosis was assessed by cell counting kit-8 (CCK-8) assay or flow cytometry assay. The releases of proinflammatory factors were investigated using enzyme-linked immunosorbent assay (ELISA). The production of malondialdehyde (MDA) and superoxide dismutase (SOD) was examined to assess oxidative stress. Total cholesterol (T-CHO) level was detected, and cholesterol efflux level was tested using a liquid scintillation counter. The putative relationship between miR-377 and circ-C16orf62 or RAB22A was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay.circ-C16orf62 expression was elevated in AS serum samples and ox-LDL-treated THP-1 cells. Apoptosis, inflammation, oxidative stress and cholesterol accumulation induced by ox-LDL were suppressed by circ-C16orf62 knockdown. Circ-C16orf62 could bind to miR-377 and thus increased the expression level of RAB22A. Rescued experiments showed that circ-C16orf62 knockdown alleviated ox-LDL-induced THP-1 cell injuries by increasing miR-377 expression, and miR-377 overexpression lessened ox-LDL-induced THP-1 cell injuries by degrading RAB22A level.In conclusion, circ-C16orf62 played a crucial role in the regulation of apoptosis, inflammation, oxidative stress and cholesterol accumulation in ox-LDL-treated human macrophages via mediating the miR-377/RAB22A axis, hinting that circ-C16orf62 might be involved in AS progression.

Targeting adipocyte-immune cell crosstalk to control breast cancer progression.

Adipocytes are crucial components of breast cancer and are involved in regulating the progression, therapeutic efficacy, and prognosis of breast cancer patients. Characterized by storing energy and producing a variety of secretory factors, adipocytes are responsible for inducing obesity and regulating the tumor immune activity. Adipocytes communicate with tumor infiltrating immune cells through the secreted adipokines, cytokines, and exosomes in the breast cancer TIME, which shapes the tumor supporting environment to facilitate the immune escape of tumor cells. In-depth studies of the crosstalk between adipocytes and TIME can not only provide a more comprehensive regulatory landscape of TIME, but also be conducive to screening novel targets for future precision targeted therapy. The aim of this review is to discuss recent studies for understanding the role of crosstalk between adipocytes and immune cells in shaping the breast cancer immune microenvironment.

Misdiagnosis of thyroid penetration caused by fishbone ingestion: a case report and literature review.

Background: Foreign body ingestion is a common occurrence. However, thyroid penetrating injury caused by fishbone migration is rare. Case Description: In this study, we present a rare misdiagnosed case of a fishbone fixed in the thyroid with a negative diagnosis on laryngoscopy examination. A 52-year-old woman experienced severe and persistent left anterior cervical pain when eating fish. Laryngoscopic imaging at an external hospital, revealed a cyst with a maximum length of 2 cm on the epiglottis, and epiglottic cyst resection under a laryngoscope was performed. The pain was not relieved, and the patient was referred to our hospital. Computed tomography and ultrasound examinations showed a sloping foreign body with a length of approximately 2.5 cm from top to bottom in the left lobe of the thyroid gland. The possibility of a penetrating fishbone injury was considered, and the foreign body was surgically removed. Postoperative drainage, fasting, and antibiotics were prescribed for 3 days, and then the patient was discharged. Follow-ups for 40 days suggested that she had recovered well without complications. Conclusions: The presence of a migratory fishbone should be considered when a patient has a history of fishbone ingestion but laryngoscopy or esophagoscopy assessment of foreign body ingestion is negative.

Horner syndrome after thyroid-related surgery: a review.

BACKGROUND: Horner syndrome (HS) is caused by damage to the cervical sympathetic nerve. HS is a rare complication after thyroidectomy. The main manifestations of HS include miosis and ptosis of the eyelids, which seriously affect esthetics and quality of life. At present, there is a lack of research on HS after thyroidectomy, and its etiology is not completely clear. This review aimed to evaluate how to reduce the incidence of HS and promote the recovery from HS as well as to provide a reference for the protection of cervical sympathetic nerves during surgery. RESULTS: HS caused by thyroid surgery is not particularly common, but it is still worthy of our attention. After searching with "Horner Syndrome," "Thyroid" as keywords, a total of 22 related cases were screened in PubMed. The results showed that open surgery, endoscopy, microwave ablation, and other surgical methods may have HS after operation. In addition, the statistics of 1213 thyroid surgeries in our hospital showed that the incidence of HS after endoscopic surgery (0.39%) was slightly higher than that after open surgery (0.29%). Further, this review analyzed potential causes of HS after thyroidectomy, so as to provide a theoretical basis for reducing its incidence. CONCLUSION: Preventing HS during thyroidectomy is a difficult problem. The close and highly variable anatomical relationship between the thyroid and cervical sympathetic nerves increases the risk of sympathetic nerve damage during thyroidectomy. Surgery and the use of energy equipment are also closely related to the occurrence of HS.

Risk factors of non-sentinel lymph node metastasis in 443 breast cancer patients with sentinel lymph node-positive.

Axillary lymph node dissection is the standard surgical procedure for breast cancer patients with sentinel lymph node (SLN) positive. In clinical practice, axillary lymph node dissection may be an unnecessary treatment for some breast cancer patients with non-sentinel lymph node (NSLN) negative. The aim of this study was to analyze the risk factors of NSLN metastasis in breast cancer patients with SLN positive. Four hundred fifty-six clinical early stage breast cancer patients with SLN positive were collected and analyzed in the oncological surgery department of Fujian Provincial Hospital during 2013 to 2018. All these patients underwent surgical treatment. The average age and tumor size of 443 patients with SLN positive breast cancer were (49.8 ± 10.8) years and (2.42 ± 0.94) cm. Univariate analysis showed that the size of primary tumor, the number of positive SLN, the number of negative SLN, the ratio of positive SLNs, and the type of metastases in SLN were the influencing factors of NSLN metastasis. Multivariate regression analysis showed that primary tumor size T > 2 cm (P < .001, OR = 2.609), the positive number of SLNs ≥3 (P = .002, OR = 5.435), the ratio of positive SLNs ≥ 50% (P = .017, OR = 1.770), and SLN macrometastases (P < 0.001, OR = 16.099) were independent risk factors for NSLN metastasis. Combined with the 4 independent risk factors, the area under the curve to predict NSLN metastasis was 0.747 > 0.7. For clinical early breast cancer with positive SLN, primary tumor size T > 2 cm,the positive number of SLNs ≥ 3, the ratio of positive SLNs ≥ 50%, and SLN macrometastases could predict NSLN metastasis well, and guide surgery to avoid overtreatment.

Risk Factors of Brain Metastasis and Prognosis in HER2-Positive Breast Cancer: A Single-Institution Retrospective Analysis from China.

Background: Brain metastasis (BM) frequently occurs in HER2-positive breast cancer (BC) patients, but the risk factors of BM in this type of patients are still unknown. Our study aims to assess the risk factors of BM and prognostic analysis in HER2-positive BC patients. Methods: Univariate analysis used t-test, chi-square test, and Fisher's exact test to find out the risk factors for BM, and multivariable analysis was done with stepwise logistic regression analysis. Prognostic data analysis was estimated by the Kaplan-Meier method. Results: A total of 228 HER2-positive BC patients were included, of whom 214 patients were postoperative metastatic patients and 14 patients were de novo stage IV patients. Through comparing the stratified variables between 51 postoperative metastatic patients with BM and 163 postoperative metastatic patients without BM, the multivariate analysis showed that age ≤40 years (OR 2.321, 95% CI: 1.089 to 4.948) and first metastatic site with lung metastasis (OR 2.168, 95% CI: 1.099 to 4.274) were independent risk factors for BM in HER2-positive BC patients. Prognostic data of all 65 HER2-positive BC patients with BM showed that the time from the diagnosis of BC to the development of breast cancer brain metastasis (BCBM) was 36.3 months (95% CI: 30.0 to 42.1 months). The time from the diagnosis of first recurrence and metastasis stage to the diagnosis of BCBM was 11.35 months (95% CI: 7.1 to 18.4 months). The time from the diagnosis of BCBM to the time of follow-up was 24.1 months (95% CI: 13.9 to 37.5 months). Up until the time of follow-up data, a total of 38 patients had died, and the time from the diagnosis of BM of these 38 patients to death was 11.0 months (95% CI: 9.0 to 20.4 months). Conclusion: The prognosis of HER2-positive BC patients with BM was poor due to the lack of effective treatments for BM. Age ≤40 years and first metastatic site with lung metastasis were the independent risk factors for BM in HER2-positive BC patients. Future research about pre-emptive medical interventions may help to improve the prognosis of HER2-positive BC patients with high risk to develop BM.

Axillary masses as clinical manifestations of male sweat gland carcinoma associated with extramammary Paget's disease and accessory breast carcinoma: two cases report and literature review.

BACKGROUND: Male cases of accessory breast carcinoma and sweat gland carcinoma associated with extramammary Paget's disease of the axilla are uncommon. In clinical diagnosis and treatment, it is necessary to determine the disease carefully and make a reasonable treatment strategy according to the patient's situation. CASE PRESENTATION: We described two male cases of the special tumor with an axillary mass as the first clinical symptom, one of which was diagnosed as accessory breast cancer and the other as sweat gland cancer associated with extramammary Paget's disease. We treated the two diseases individually in the hopes of providing a reference for the diagnosis and management of diseases with axillary nodules as the initial symptom. CONCLUSIONS: The reports of these two cases can provide reference and corresponding thinking for clinical differentiation of axillary lymphadenopathy caused by different causes and subsequent treatment. These two cases may further enrich the database of rare cases and provide some ideas for the treatment of axillary lymphadenopathy caused by different causes.

Cytochalasin Q exerts anti-melanoma effect by inhibiting creatine kinase B.

Due to the pivotal role of microfilament in cancer cells, targeting microfilaments with cytochalasins is considered a promising anticancer strategy. Here, we obtained cytochalasin Q (CQ) from Xylaria sp. DO1801, the endophytic fungi from the root of plant Damnacanthus officinarum, and discovered its anti-melanoma activity in vivo and in vitro attributing to microfilament depolymerization. Mechanistically, CQ directly bound to and inactivated creatine kinase B (CKB), an enzyme phosphorylating creatine to phosphocreatine (PCr) and regenerating ATP to cope with high energy demand, and then inhibited the creatine metabolism as well as cytosolic glycolysis in melanoma cells. Preloading PCr recovered ATP generation, reversed microfilament depolymerization and blunted anti-melanoma efficacy of CQ. Knockdown of CKB resulted in reduced ATP level, perturbed microfilament, inhibited proliferation and induced apoptosis, and manifested lower sensitivity to CQ. Further, we found that either CQ or CKB depletion suppressed the PI3K/AKT/FoxO1 pathway, whereas 740Y-P, a PI3K agonist, elevated protein expression of CKB suppressed by CQ. Taken together, our study highlights the significant anti-melanoma effect and proposes a PI3K/AKT/FoxO1/ CKB feedback circuit for the activity of CQ, opening new opportunities for current chemotherapy.

Targeting the Key Enzymes of Abnormal Fatty Acid ß-oxidation as a Potential Strategy for Tumor Therapy.

Fatty acid metabolism has attracted extensive attention for its key role in the occurrence and development of tumors. Fatty acids not only participate in the biosynthesis of phospholipids in the membrane to overcome the demand for rapidly proliferating membrane lipids but also provide ATP, signaling molecules, and NADPH through ß-oxidation to maintain tumor survival and growth. However, the specific role of fatty acid ß-oxidation in tumors and the description of multiple potential targets in this process are not comprehensive and systematic. Therefore, this review summarizes the function of fatty acid ß-oxidation in tumors and studies of key enzymes that catalyze related reactions in various stages to improve the overall understanding of fatty acid ß-oxidation and search for novel tumor treatment strategies and ideas.

BAHD1 serves as a critical regulator of breast cancer cell proliferation and invasion.

Breast cancer patients with lymphatic metastasis suffer from poor prognoses. There is an urgent need for controlling lymph node metastasis, but it has proven challenging so far. Here, we implemented LASSO analysis of The Cancer Genome Atlas database to identify genes related to lymph node metastasis and prognosis, and 15 genes were selected. We constructed a functional protein association network and univariate Cox regression to identify significant genes. The results showed that BAHD1 could be predictive of lymph node metastasis as well as prognosis. In vitro studies demonstrated that BAHD1 exerted appreciable effects on the proliferation, migration, and invasion capacity of breast cancer cells. Furthermore, downregulation of BAHD1 induced cell cycle arrest in G1 phase. Additionally, the mRNA levels of CCND1, CDK1 and YWHAZ were decreased upon BAHD1 silencing. These findings indicate that the expression of BAHD1 is essential in the progression of breast cancer, which may provide novel therapeutic and diagnostic clues and insights into the prevention of lymph node metastasis in breast cancer.

Diagnostic and prognostic value of tumor-infiltrating B cells in lymph node metastases of papillary thyroid carcinoma.

Lymph node metastases are strongly associated with unfavorable prognosis in papillary thyroid carcinoma (PTC) patients. However, there are few sensitive or specific indicators that can diagnose or predict lymph node metastases in PTC. The objective of our study was to identify reliable indicators for the diagnosis and prediction of lymph node metastases of PTC. The PTC data set was obtained from The Cancer Genome Atlas (TCGA) cohort. Information on tumor-infiltrating immune cells in PTC was acquired using single-sample gene set enrichment analysis (ssGSEA). Then, the progression-free survival (PFS) rates of PTC patients were evaluated by Kaplan-Meier curves. A tissue microarray including 58 normal thyroid tissues and 57 PTC tissues was processed for CD19 immunohistochemistry staining. Finally, evaluation of phenotype permutations was performed using gene set enrichment analysis (GSEA). There was an appreciable association between immune infiltration and lymph node metastases in PTC. Among those immune cells, B cells and cytotoxic cells showed significant predictive accuracy for lymph node metastases in PTC. Tumor-infiltrating B cells and NK cells were associated with favorable prognosis, while tumor-associated NK CD56bright cells were correlated with poor prognosis in PTC patients. IHC analyses of PTC further confirmed a notably negative correlation between B cell infiltration and lymph node metastases in PTC. Additionally, mutations in BRAF, a dominant cause of tumor mutation burden (TMB), were positively correlated with reduced B cell infiltration and lymph node metastases in PTC. GSEA revealed that epithelial-mesenchymal transition, IL-6/JAK/STAT3 signaling, the inflammatory response, and TNF-α signaling via the NFκB pathway were remarkably suppressed pathways in patients with BRAF mutations. Tumor-associated lymphocytic infiltration, especially B cell infiltration, provides diagnostic and prognostic value for lymph node metastases in PTC.

Metabolic heterogeneity and immunocompetence of infiltrating immune cells in the breast cancer microenvironment (Review).

Breast cancer is one of the most common malignancies in women and is characterized by active immunogenicity. Immune cell infiltration plays an important role in the development of breast cancer. The degree of infiltration influences both the response to and effect of treatment. However, immune infiltration is a complex process. Differences in oxygen partial pressure, blood perfusion and nutrients in the tumor microenvironment (TME) suggest that infiltrating immune cells in different sites experience different microenvironments with corresponding changes in the metabolic mode, that is, immune cell metabolism is heterogenous in the TME. Furthermore, the present review found that lipid metabolism can support the immunosuppressive microenvironment in breast cancer based on a review of published literature. Research in this field is still ongoing; however, it is vital to understand the metabolic patterns and effects of different microenvironments for antitumor therapy. Therefore, this review discusses the metabolic responses of various immune cells to different microenvironments in breast cancer and provides potentially meaningful insights for tumor immunotherapy.

Knockdown of PC4 increases chemosensitivity of Oxaliplatin in triple negative breast cancer by suppressing mTOR pathway.

As a multifunctional nuclear protein, the human positive cofactor 4 (PC4) is highly expressed in various tumors including breast cancer and has potential roles in cancer development and progression. However, the functional signatures and molecular mechanisms of PC4 in triple negative breast cancer (TNBC) progression and chemotherapeutic response are still unknown. In this study, we found that PC4 is significantly upregulated in TNBC cells compared with non-TNBC cells, implying its potential role in TNBC. Then, in vivo and in vitro studies revealed that knockdown of PC4 increased chemosensitivity of Oxaliplation (Oxa) in TNBC by suppressing mTOR pathway. Therefore, our findings demonstrated the signatures and molecular mechanisms of PC4 in TNBC chemotherapeutic response, and indicated that PC4 might be a promising therapeutic target for TNBC.

Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer.

Forkhead box transcription factor M1 (FOXM1) is a proliferation-associated transcription factor involved in tumorigenesis through transcriptional regulation of its target genes in various cells, including dendritic cells (DCs). Although previous work has shown that FOXM1 enhances DC maturation in response to house dust mite allergens, it is not known whether FOXM1 affects DC maturation in the context of tumor-specific immunity. In this study, we examined the central role of FOXM1 in regulating bone marrow-derived dendritic cell (BMDC) maturation phenotypes and function in pancreatic cancer and colon cancer. FOXM1 retarded maturation phenotypes of BMDCs, inhibited promotion of T-cell proliferation, and decreased interleukin-12 (IL-12) p70 in tumor-bearing mice (TBM). Notably, FOXM1 expression was epigenetically regulated by dimethylation on H3 lysine 79 (H3K79me2), a modification present in both tumor cells and BMDCs. Increased H3K79me2 enrichment was observed at the FOXM1 promoter in both BMDCs from TBM, and in BMDCs from wild-type mice cultured with tumor-conditioned medium that mimics the tumor microenvironment (TME). Furthermore, inhibition of the H3K79 methyltransferase DOT1L not only decreased enrichment of H3K79me2, but also downregulated expression of FOXM1 and partially reversed its immunosuppressive effects on BMDCs. Furthermore, we found that FOXM1 upregulated transcription of Wnt family number 5A (Wnt5a) in BMDCs in vitro; we also observed that exogenous Wnt5a expression abrogated BMDC maturation phenotypes by inhibiting FOXM1 and H3K79me2 modification. Therefore, our results reveal that upregulation of FOXM1 by H3K79me2 in pancreatic cancer and colon cancer significantly inhibits maturation phenotypes and function of BMDCs through the Wnt5a signaling pathway, and thus provide novel insights into FOXM1-based antitumor immunotherapy.