Visibility of esophageal squamous cell carcinoma under iodine staining on texture and color enhancement imaging.

Objective: Iodine staining on white light imaging (WLI) is the gold standard for detecting and demarcating esophageal squamous cell carcinoma (ESCC). We examined the effects of texture and color enhancement imaging (TXI) on improving the endoscopic visibility of ESCC under iodine staining. Methods: Twenty ESCC lesions that underwent endoscopic submucosal dissection were retrospectively included. The color difference between ESCC and the surrounding mucosa (ΔEe) on WLI, TXI, and narrow-band imaging was assessed, and ΔEe under 1% iodine staining on WLI and TXI. Furthermore, the visibility grade determined by endoscopists was evaluated on each imaging. Result: The median ΔEe was greater on TXI than on WLI (14.53 vs. 10.71, respectively; p < 0.005). Moreover, the median ΔEe on TXI under iodine staining was greater than the median ΔEe on TXI and narrow-band imaging (39.20 vs. 14.53 vs. 16.42, respectively; p < 0.005 for both). A positive correlation in ΔEe under iodine staining was found between TXI and WLI (correlation coefficient = 0.61, p < 0.01). Moreover, ΔEe under iodine staining on TXI in each lesion was greater than the corresponding ΔEe on WLI. The visibility grade assessed by endoscopists on TXI was also significantly greater than that on WLI under iodine staining (p < 0.01). Conclusions: The visibility of ESCC after iodine staining was greater on TXI than on WLI.

Diffuse coexpression of thyroid transcription factor-1 and p40 in a non-small cell carcinoma of the lung: Second case in the female population / Coexpresión difusa del factor de transcripción tiroidea 1 y p40 en un carcinoma de célula no pequeña del pulmón: segundo caso en la población de sexo femenino

Some non-small cell carcinomas of the lung can express TTF1 and p40 in the same tumor cells. This event has been described in only six cases prior to this one, and only in one other female. It is an extraordinary event that appears as a new entity yet to be defined. The case presented is a woman with a non-small cell lung carcinoma with diffuse coexpression of TTF1 and p40 in the same cells. (AU)

Algunos carcinomas de célula no pequeña del pulmón pueden expresar TTF1 y p40 en las mismas células tumorales. Este evento se ha descrito únicamente en 6 casos anteriores a este, y solo en otra persona del sexo femenino. Se trata de un evento extraordinario que se muestra como una nueva entidad todavía por definir. El caso que se presenta versa sobre una mujer con un carcinoma de pulmón de célula no pequeña con coexpresión difusa en las mismas células de TTF1 y p40. (AU)

The involvement of epidermal growth factor receptor/protein kinase B signaling in the tumor intrinsic PD-L1-induced malignant potential of oral squamous cell carcinoma.

BACKGROUND: Various antigen-presenting cells and tumor cells-expressing PD-L1 inhibits antitumor immune responses in the tumor microenvironment. Recently, numerous studies have shown that tumor cell intrinsic PD-L1 also plays important roles in tumor growth and progression. On the other hand, oral squamous cell carcinoma (OSCC) cells overexpress epidermal growth factor receptor (EGFR) and EGFR signal pathway exacerbates tumor progression. Therefore, this study assessed whether tumor-intrinsic PD-L1 facilitates malignant potential of OSCC cells through regulation of EGFR signaling. METHODS: Two OSCC cell lines, SAS and HSC-3, were transfected with PD-L1 and EGFR-specific small interfering RNA (siRNA). Influences of PD-L1 knockdown on malignant potentials of OSCC cells were examined by Cell Counting kit-8 assay, transwell assay, sphere formation assay, flow cytometry, and Western blot. Effects of PD-L1 and EGFR knockdown on each expression were examined by quantitative real-time PCR (qRT-PCR), Western blot, and flow cytometry. RESULTS: Transfection of an PD-L1-siRNA into OSCC cells decreased the abilities of proliferation, stemness, and mobility of these cells significantly. PD-L1 knockdown also decreased EGFR expression through the promotion of proteasome- and lysosome-mediated degradation and following activation of the EGFR/protekin kinase B (AKT) signal pathway. Meanwhile, EGFR knockdown did not influence PD-L1 expression in SAS and HSC-3 cells, but treatment with a recombinant human EGF induced its expression. Treatment with erlotinib and cetuximab suppressed rhEGF-induced PD-L1 expression and localization in the cellular membrane of both OSCC cells. CONCLUSION: OSCC cells-expressing PD-L1 induced by EGF stimulation may promote malignancy intrinsically via the activation of the EGFR/AKT signaling cascade.

Assessment of the association of myofibroblasts and structural components of the extracellular matrix with histopathological parameters of actinic cheilitis and lower lip squamous cell carcinoma.

BACKGROUND: To evaluate the presence of myofibroblasts (MFs) in the development of lip carcinogenesis, through the correlation of clinical, histomorphometric and immunohistochemical parameters, in actinic cheilitis (ACs) and lower lip squamous cell carcinomas (LLSCCs). METHODS: Samples of ACs, LLSCCs, and control group (CG) were prepared by tissue microarray (TMA) for immunohistochemical TGF-ß, α-SMA, and Ki-67 and histochemical hematoxylin and eosin, picrosirius red, and verhoeff van gieson reactions. Clinical and microscopic data were associated using the Mann-Whitney, Kruskal-Wallis/Dunn, and Spearman correlation tests (SPSS, p < 0.05). RESULTS: ACs showed higher number of α-SMA+ MFs when compared to CG (p = 0.034), and these cells were associated with the vertical expansion of solar elastosis (SE) itself (p = 0.027). Areas of SE had lower deposits of collagen (p < 0.001), immunostaining for TGF-ß (p < 0.001), and higher density of elastic fibers (p < 0.05) when compared to areas without SE. A positive correlation was observed between high-risk epithelial dysplasia (ED) and the proximity of SE to the dysplastic epithelium (p = 0.027). LLSCCs showed a higher number of α-SMA+ MFs about CG (p = 0.034), as well as a reduction in the deposition of total collagen (p = 0.009) in relation to ACs and CG. There was also a negative correlation between the amount of α-SMA+ cells and the accumulation of total collagen (p = 0.041). Collagen and elastic density loss was higher in larger tumors (p = 0.045) with nodal invasion (p = 0.047). CONCLUSIONS: Our findings show the possible role of MFs, collagen fibers, and elastosis areas in the lip carcinogenesis process.

Comparative clinicopathological study of the main anatomic locations of oral squamous cell carcinoma.

OBJECTIVE: To analyze the clinicopathological and evolutionary profile of the main locations of oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: This is a retrospective study on 133 patients treated for OSCC. The group was composed of 48 women and 85 men, with a mean age 63.9 ± 12.73 years. Most cases involved the lingual border of tongue (63), followed by the gingiva (36) and the floor of mouth (34). A comparative analysis was performed using multinomial regression. RESULTS: There were significant differences regarding age, sex, tobacco and alcohol consumption, liver pathology, oral potentially malignant disorders, and bone and perineural invasion. In multivariate regression, tobacco consumption, and bone invasion remained significant. There were no significant differences in relation to prognosis. CONCLUSION: The location of OSCC is an important factor in the clinicopathological assessment of this neoplasm. The main locations of OSCC show differential etiopathogenic and clinicopathological aspects. Tobacco consumption has a great relevance in the floor of mouth; nonetheless, it is less important in the tongue border and the gum, which suggests other pathogenic factors. It is necessary to consider the anatomical location of OSCC in preventive protocols, with the aim of reducing its high mortality.

Impacts of tumor microenvironment during neoadjuvant chemotherapy in patients with esophageal squamous cell carcinoma.

With the advent of immune checkpoint inhibitors (ICIs), a better understanding of tumor microenvironment (TME) is becoming crucial in managing esophageal squamous cell carcinoma (ESCC) patients. We investigated the survival impact of TME status and changes in patients with ESCC who underwent neoadjuvant chemotherapy (NAC) followed by surgery (n = 264). We examined immunohistochemical status (CD4+, CD8+, CD20+, Foxp3+, HLA class-1+, CD204+, and programmed death ligand-1 [PD-L1+]) on 264 pre-NAC and 204 paired post-NAC specimens. Patients were classified by their pre- and post-NAC immune cell status and their changes following NAC. Our findings showed that pre-NAC TME status was not significantly associated with survival outcomes. In contrast, post-NAC TME status, such as low level of T cells, CD4+ T cells, and high PD-L1 combined positive score (CPS), were significantly associated with poor overall survival (OS). Notably, TME changes through NAC exerted significant survival impacts; patients with consistently low levels of T cells, low levels of CD4+ T cells, or high levels of PD-L1 (CPS) had very poor OS (3-year OS: 35.5%, 40.2%, and 33.3%, respectively). Tumor microenvironment changes of consistently low T cells, low CD4+ T cells, and high PD-L1 were independent predictors of poor OS in multivariate Cox hazards analyses, while factors indicating post-NAC status (T cells, CD4+, and PD-L1 [CPS]) alone were not. Therefore, we suggest that the consistently low T/high PD-L1 group could benefit from additional therapies, such as ICIs, and the importance of stratification by the TME, which has recently been recognized.

Association between waterpipe smoking and lung cancer: a multicentre case-control study in Iran.

OBJECTIVES: This study investigated the association between lung cancer and waterpipe smoking, which is an emerging global public health concern. STUDY DESIGN: Multicentre case-control study. METHODS: This study included 627 cases and 3477 controls from the Iranian Study of Opium and Cancer (IROPICAN) study, which was conducted between 2017 and 2020. One frequency-matched control for each lung cancer patient was selected by age, gender and residential place; however, this study used controls of four cancer types in the analyses. The multivariable logistic regression model estimated the odds ratio (OR) and 95% confidence intervals (CIs). Additional analyses were performed among 181 lung cancer cases and 2141 controls who were not cigarette smokers or opium or nass/pipe users. RESULTS: The odds of lung cancer were higher among waterpipe smokers than never-smokers (OR = 1.3, 95% CI: 1.0-1.7). Results showed a higher OR of lung cancer for those who smoked the waterpipe daily (OR = 2.1, 95% CI: 1.4-3.0), smoked more than two heads per day (OR = 2.7, 95% CI: 1.8-4.0), had smoked for >20 years (OR = 1.9, 95% CI: 1.3-2.7), smoked more than 20 head-years (OR = 2.8, 95% CI: 1.9-4.1) and initiated smoking before the age of 30 years (OR = 1.7, 95% CI: 1.1-2.5). The association was only statistically significant for squamous cell carcinomas (OR = 1.8, 95% CI 1.2-2.7). Furthermore, this study observed a higher OR of lung cancer among exclusive waterpipe smokers (OR = 2.3, 95% CI: 1.6, 3.5). CONCLUSIONS: Waterpipe smoking was associated with an increased risk of lung cancer. The association was stronger with higher frequency, duration and intensity of exposure to waterpipe smoking. The association increases in exclusive waterpipe smokers, which is likely due to controlling for residual confounding by cigarette smoking and opium consumption, and higher exposure levels in this subpopulation.

An investigative meta-analysis on the effectiveness and safety of integrating VEGF/VEGFR inhibitors with PD-1/PD-L1 inhibitors in cases with R/M HNSCC.

OBJECTIVES: Exploration into the use of vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) inhibitors alongside programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors has been undertaken for treating recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). We conducted a meta-analysis to provide a more precise assessment of the efficacy and safety of this integrated approach in managing R/M HNSCC. METHODS: A systematic exploration encompassing PubMed, Embase, the Cochrane Library, and Web of Science databases was undertaken to figure out relevant studies. It was attempted to analyze critical endpoints, such as overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) utilizing a random-effects model. RESULTS: Eleven studies, encompassing 413 patients, were analyzed. The combined data revealed an ORR of 41 % (95 % CI: 34-49 %), a DCR of 67 % (95 % CI: 51-83 %), a median PFS of 5.87 months (95 % CI: 3.90-7.85), and a median OS of 9.63 months (95 % CI: 6.78-12.49). Furthermore, the rates for 1-year PFS and OS were 45 % (95 % CI: 27-64 %) and 65 % (95 % CI: 49-81 %), respectively. The occurrence of grade 3 or higher adverse events related to the drugs was 20 % (95 % CI: 10-30 %). Subgroup analysis within the tyrosine kinase inhibitor (TKI) group revealed an ORR of 47 % (95 % CI: 39 %-55 %) and a DCR of 67 % (95 % CI: 46 %-88 %). CONCLUSIONS: In summary, combining VEGF/VEGFR inhibitors with PD-1/PD-L1 inhibitors shows considerable effectiveness with manageable side effects in cases with R/M HNSCC. SYSTEMATIC REVIEW REGISTRATION: Registered with the International Prospective Register of Systematic Reviews, identifier CRD42023486345.

Surveillance for metachronous cancers after endoscopic resection of esophageal squamous cell carcinoma.

The literature pertaining to surveillance following treatment for esophageal squamous cell carcinoma (SCC) was reviewed and summarized, encompassing the current status and future perspectives. Analysis of the standardized mortality and incidence ratios for these cancers indicates an elevated risk of cancer in the oral cavity, pharynx, larynx, and lungs among patients with esophageal SCC compared to the general population. To enhance the efficacy of surveillance for these metachronous cancers, risk stratification is needed. Various factors, including multiple Lugol-voiding lesions, multiple foci of dilated vascular areas, young age, and high mean corpuscular volume, have been identified as predictors of metachronous SCCs. Current practice involves stratifying the risk of metachronous esophageal and head/neck SCCs based on the presence of multiple Lugol-voiding lesions. Endoscopic surveillance, scheduled 6-12 months post-endoscopic resection, has demonstrated effectiveness, with over 90% of metachronous esophageal SCCs treatable through minimally invasive modalities. Narrow-band imaging emerges as the preferred surveillance method for esophageal and head/neck SCC based on comparative studies of various imaging techniques. Innovative approaches, such as artificial intelligence-assisted detection systems and radiofrequency ablation of high-risk background mucosa, may improve outcomes in patients following endoscopic resection.

Treatment with (chemo)-radiation in old patients (≥76 years of age) with newly diagnosed non-metastatic squamous cell cancer of the head and neck region: real-world data from a tertiary referral center.

Purpose: Treatment of patients with cancer of the head and neck region is in focus in a multitude of studies. Of these patients, one patient group, those aged 76 and more, is mostly underrepresented despite requiring thorough and well-reasoned treatment decisions to offer curative treatment. This study investigates real-world data on curative treatment of old (≥76 years) patients with newly diagnosed squamous cell carcinoma of the head and neck region (HNSCC). Patients and methods: Between January 2010 and December 2021, we identified 71 patients older than 76 years with newly diagnosed HNSCC and cM0 at the Department of Radiation Oncology of the University Hospital of Erlangen-Nuremberg. Using electronic medical records, we analyzed treatment patterns and outcomes in terms of overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) rate. Additionally, we performed univariate risk analysis and Cox regression in order to identify predictive factors associated with the abovementioned treatment outcomes. Results: The median follow-up was 18 months. OS was 83%, 79%, and 72% after 1 year, 2 years, and 3 years, respectively. PFS was 69%, 54%, and 46% after 1 year, 2 years, and 3 years, respectively. A total of 34 (48%) patients were treated with standard therapy according to current guidelines. The reasons for deviation from standard therapy before or during treatment were as follows: unfitness for cisplatin-based chemotherapy (n = 37), reduction of chemotherapy (n = 3), and dose reduction/interruption of radiotherapy (n = 8). Carboplatin-based systemic therapy showed improved PFS compared to cisplatin or cetuximab (60 vs. 28 vs. 15 months, p = 0.037) but without impact on OS (83 vs. 52 vs. 38 months, p = 0.807). Oropharyngeal tumor localization (p = 0.026) and combined treatment (surgery and postoperative treatment) (p = 0.008) were significant predictors for a better OS. In multivariate analysis, oropharyngeal tumor localization (p = 0.011) and combined treatment (p = 0.041) showed significantly increased PFS. After 1 year, 2 years, and 3 years, the cumulative incidence of locoregional recurrences (LRRs) was 13%, 24%, and 27%, respectively, and was significantly decreased in patients with oropharyngeal tumor localization (p = 0.037). Conclusions: Adherence to treatment protocols for radiotherapy alone in old patients with HNSCC is good, whereas the application of concurrent chemotherapy often deviates from guidelines in terms of de-escalation. An important risk factor for decreased OS, PFS, and a higher rate of LRR appears to be non-oropharyngeal tumor location in old patients.

Mechanism study of lncRNA RMRP regulating esophageal squamous cell carcinoma through miR-580-3p/ATP13A3 axis.

OBJECTIVE: It is well-known that lncRNAs regulate energy metabolism in tumors. This study focused on the action of RMRP on esophageal squamous cell carcinoma (ESCC) cell proliferation, apoptosis, and glycolysis. METHODS: In the resected ESCC tissues and adjacent tissues from patients, RMRP/miR-580-3p/ATP13A3 expressions were evaluated. ESCC cell proliferation rates and apoptotic rates were measured by CCK-8 and flow cytometry, respectively. Apoptosis related markers were examined by Western blot. Moreover, glucose uptake, lactic acid, and ATP were measured by commercial kits, whereas HK2 and PKM2 were evaluated by Western blot to study ESCC cell glycolysis. Finally, the editing program of RMRP/miR-580-3p/ATP13A3 was translated by luciferase reporter assay and RIP analysis. RESULTS: RMRP and ATP13A3 were induced, while miR-580-3p was reduced in their expression in ESCC tissues. Silencing RMRP reduced proliferation, glycolysis, and anti-apoptosis ability of ESCC cells. RMRP sequestered miR-580-3p to target ATP13A3. Silenced ATP13A3 or overexpressed miR-580-3p rescued overexpressed RMRP-mediated promotion of proliferation, glycolysis, and anti-apoptosis of ESCC cells. CONCLUSION: RMRP accelerates ESCC progression through the miR-580-3p/ATP13A3 axis, renewing a reference for lncRNA-based therapies for tumors.

CD271 mRNA/hnRNPA2B1 complex promotes proliferation and stemness in oral and head and neck squamous cell carcinoma.

RNAs, such as noncoding RNA, microRNA, and recently mRNA, have been recognized as signal transduction molecules. CD271, also known as nerve growth factor receptor, has a critical role in cancer, although the precise mechanism is still unclear. Here, we show that CD271 mRNA, but not CD271 protein, facilitates spheroid cell proliferation. We established CD271-/- cells lacking both mRNA and protein of CD271, as well as CD271 protein knockout cells lacking only CD271 protein, from hypopharyngeal and oral squamous cell carcinoma lines. Sphere formation was reduced in CD271-/- cells but not in CD271 protein knockout cells. Mutated CD271 mRNA, which is not translated to a protein, promoted sphere formation. CD271 mRNA bound to hnRNPA2B1 protein at the 3'-UTR region, and the inhibition of this interaction reduced sphere formation. In surgical specimens, the CD271 mRNA/protein expression ratio was higher in the cancerous area than in the noncancerous area. These data suggest CD271 mRNA has dual functions, encompassing protein-coding and noncoding roles, with its noncoding RNA function being predominant in oral and head and neck squamous cell carcinoma.

Diagnostic value of 18F-FDG PET/CT versus diffusion-weighted MRI in detection of residual or recurrent tumors after definitive (chemo) radiotherapy for laryngeal and hypopharyngeal squamous cell carcinoma: A prospective study.

BACKGROUND: Despite advances in treatment, residual or recurrent tumors after definitive (chemo) radiotherapy for laryngeal and hypopharyngeal squamous cell carcinoma (SCC) remain a challenge in clinical management and require accurate and timely detection for optimal salvage therapy. This study aimed to compare the diagnostic value of Fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and diffusion-weighted magnetic resonance imaging (DW-MRI) in detecting residual or recurrent tumors after definitive (chemo) radiotherapy for laryngeal and hypopharyngeal SCC. METHODS: A prospective study was conducted on 30 patients who presented with new symptoms after definitive (chemo) radiotherapy for laryngeal (n = 21) and hypopharyngeal (n = 9) carcinoma. Both 18F-FDG PET/CT and DW-MRI were performed and histopathologic analysis served as the standard of reference. RESULTS: Histopathology showed 20 patients as positive and 10 as negative for tumors. 18F-FDG PET/CT detected all tumors correctly but was falsely positive in one case. DW-MRI detected tumors in 18 out of 20 positive patients and correctly excluded tumors in all negative patients. The sensitivity and specificity of 18F-FDG PET/CT were 100% and 90%, respectively, while the values for DW-MRI were 90% and 100%, respectively. CONCLUSIONS: The study concludes that 18F-FDG PET/CT is slightly superior to DW-MRI in detecting residual or recurrent tumors after definitive (chemo) radiotherapy for laryngeal and hypopharyngeal SCC. The combined use of 18F-FDG PET/CT and DW-MRI can potentially improve specificity in therapy response evaluation.

Risk Factors for Complications in Patients Undergoing Temporal Bone Resection and Neck Dissection: Insights From a National Database.

BACKGROUND: Temporal bone resection (TBR) with or without neck dissection (ND) is performed for otologic malignancies with occult or clinical cervical lymph node metastases. To date, characterization of post-operative complications in single institution case series may be non-representative of real-world outcomes. Here, we used data from the National Inpatient Sample (NIS) to comprehensively assess the complications encountered, their frequencies, and to identify underlying risk factors to improve future outcomes. METHODS: The population was patients undergoing TBR and ND derived from the NIS between the years of 2017 and 2019. We utilized ICD-10 diagnosis codes to identify patients with post-operative complications, those discharged to non-home facilities (DNHF), and those with increased length of stay (LOS). Multivariable regression was performed to identify significant variables related to the above outcomes. RESULTS: Ninety of 277 patients that underwent LTBR with ND had postoperative complications. Wound complications were the most frequent complication, occurring in 11 (4%) of patients, followed by CSF leak (n = 6; 2.2%), with acute respiratory failure being the most common medical complication (n = 4; 1.4%). Sixteen percent (45/277) were discharged to a facility besides home. Dementia (OR = 7.96; CI95 3.62-17.48), anemia (OR = 2.39; CI95 1.15-4.99), congestive heart failure (OR = 5.31; CI95 1.82-15.45), COPD (OR = 3.70; CI95 1.35-10.16), and history of prior stroke (OR = 8.50; CI95 1.55-46.68) increased the odds of DNHF. When evaluating LOS (median = 5 days, IQR = 1, 9), anemia (OR = 5.49; CI95 2.86-10.52), and Medicaid insurance (OR = 3.07; CI95 1.06-10.52) were found to increase the LOS. CONCLUSIONS: The vast majority of patients undergoing LTBR with ND have no complications and are discharged within a week. Liver disease is a risk factor for medical complications and increased charges. Patients with dementia or a prior stroke are at risk for DNHF, and those with prior anemia are at risk for a wound complication. LAY SUMMARY: This study identified factors related to worse post-operative outcomes in patients undergoing temporal bone resection and neck dissection. Although safe for most patients, an existing diagnosis of liver disease, stroke, dementia, and anemia specifically are at risk for developing negative outcomes. LEVEL OF EVIDENCE: 3.

Potential treatment of squamous cell carcinoma by targeting heparin-binding protein 17/fibroblast growth factor-binding protein 1 with vitamin D3 or eldecalcitol.

Heparin-binding protein 17 (HBp17), first purified in 1991 from the conditioned medium of the human A431 squamous cell carcinoma (SCC) cell line, was later renamed fibroblast growth factor-binding protein 1 (FGFBP-1). HBp17/FGFBP-1 is specifically expressed and secreted by epithelial cells, and it reversibly binds to fibroblast growth factor (FGF)-1 and FGF-2, as well as FGFs-7, -10, and -22, indicating a crucial involvement in the transportation and function of these FGFs. Our laboratory has investigated and reported several studies to elucidate the function of HBp17/FGFBP-1 in SCC cells and its potential as a molecular therapeutic target. HBp17/FGFBP-1 transgene exoression in A431-4 cells, a clonal subline of A431 that lacks tumorigenicity and does not express HBp17/FGFBP-1, demonstrated a significantly enhanced proliferation in vitro compared with A431-4 cells, and it acquired tumorigenicity in the subcutis of nude mice. Knockout (KO) of the HBp17/FGFBP-1 by genome editing significantly suppressed tumor growth, cell motility, and tumorigenicity compared with control cells. A comprehensive analysis of expressed molecules in both cell types revealed that molecules that promote epithelial cell differentiation were highly expressed in HBp17/FGFBP-1 KO cells. Additionally, we reported that 1α,25(OH)2D3 or eldecalcitol (ED-71), which is an analog of 1α,25(OH)2D3, suppresses HBp17/FGFBP-1 expression and tumor growth in vitro and in vivo by inhibiting the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway. Here, we discuss the prospects of molecular targeted therapy targeting HBp17/FGFBP-1 with 1α,25(OH)2D3 or ED71 in SCC and oral SCC.

Radiation-induced upregulation of FGL1 promotes esophageal squamous cell carcinoma metastasis via IMPDH1.

BACKGROUND: While radiation therapy remains pivotal in esophageal squamous cell carcinoma (ESCC) treatment, the perplexing phenomenon of post-radiation metastasis presents a formidable clinical challenge. This study investigates the role of fibrinogen-like protein 1 (FGL1) in driving ESCC metastasis following radiation exposure. METHODS: FGL1 expression in post-radiation ESCC cells was meticulously examined using qRT-PCR, western blotting, and immunofluorescence. The impact of FGL1 on ESCC cell invasion and migration was assessed through Transwell and wound healing assays. In vivo, the metastatic potential of ESCC in response to FGL1 was scrutinized using nude mice models. Comprehensive RNA sequencing and functional experiments elucidated the intricate mechanism associated with FGL1. RESULTS: Radiation induced upregulation of FGL1 in ESCC cells through FOXO4, intensifying ESCC cell invasion and migration. Targeted knockdown of FGL1 effectively alleviated these characteristics both in vitro and in vivo. FGL1 depletion concurrently suppressed IMPDH1 expression. Rescue experiments underscored that IMPDH1 knockdown robustly reversed the pro-invasive effects induced by FGL1 in ESCC cells. ESCC tissues exhibited heightened IMPDH1 mRNA levels, demonstrating a correlation with patient survival. CONCLUSIONS: Radiation-induced upregulation of FGL1 propels ESCC metastasis through IMPDH1, proposing a potential therapeutic target to mitigate post-radiotherapy metastasis in ESCC patients.

MUC1 promotes cervical squamous cell carcinoma through ERK phosphorylation-mediated regulation of ITGA2/ITGA3.

In contrast to the decreasing trends in developed countries, the incidence and mortality rates of cervical squamous cell carcinoma in China have increased significantly. The screening and identification of reliable biomarkers and candidate drug targets for cervical squamous cell carcinoma are urgently needed to improve the survival rate and quality of life of patients. In this study, we demonstrated that the expression of MUC1 was greater in neoplastic tissues than in non-neoplastic tissues of the cervix, and cervical squamous cell carcinoma patients with high MUC1 expression had significantly worse overall survival than did those with low MUC1 expression, indicating its potential for early diagnosis of cervical squamous cell carcinoma. Next, we explored the regulatory mechanism of MUC1 in cervical squamous cell carcinoma. MUC1 could upregulate ITGA2 and ITGA3 expression via ERK phosphorylation, promoting the proliferation and metastasis of cervical cancer cells. Further knockdown of ITGA2 and ITGA3 significantly inhibited the tumorigenesis of cervical cancer cells. Moreover, we designed a combination drug regimen comprising MUC1-siRNA and a novel ERK inhibitor in vivo and found that the combination of these drugs achieved better results in animals with xenografts than did MUC1 alone. Overall, we discovered a novel regulatory pathway, MUC1/ERK/ITGA2/3, in cervical squamous cell carcinoma that may serve as a potential biomarker and therapeutic target in the future.

MUC1 is overexpressed in cervical squamous cell carcinoma. MUC1 regulates ERK phosphorylation, and subsequently upregulates ITGA2 and ITGA3 expression to promote tumorigenesis in cervical squamous cell carcinoma. A combination drug regimen targeting MUC1 and ERK achieved better results compared than MUC1 alone.

Targeting histone deacetylases in head and neck squamous cell carcinoma: molecular mechanisms and therapeutic targets.

The onerous health and economic burden associated with head and neck squamous cell carcinoma (HNSCC) is a global predicament. Despite the advent of novel surgical techniques and therapeutic protocols, there is an incessant need for efficacious diagnostic and therapeutic targets to monitor the invasion, metastasis and recurrence of HNSCC due to its substantial morbidity and mortality. The differential expression patterns of histone deacetylases (HDACs), a group of enzymes responsible for modifying histones and regulating gene expression, have been demonstrated in neoplastic tissues. However, there is limited knowledge regarding the role of HDACs in HNSCC. Consequently, this review aims to summarize the existing research findings and explore the potential association between HDACs and HNSCC, offering fresh perspectives on therapeutic approaches targeting HDACs that could potentially enhance the efficacy of HNSCC treatment. Additionally, the Cancer Genome Atlas (TCGA) dataset, CPTAC, HPA, OmicShare, GeneMANIA and STRING databases are utilized to provide supplementary evidence on the differential expression of HDACs, their prognostic significance and predicting functions in HNSCC patients.

Molecular characterization of the evolution of premalignant lesions in the upper aerodigestive tract.

Introduction: Early relapse and development of metastatic disease are some of the primary reasons for the poor prognosis of patients with head and neck squamous cell carcinoma (HNSCC). HNSCC is a heterogeneous disease which may develop in large premalignant fields of genetically altered cells. Yet knowing which individuals will progress and develop clinically significant cancers during their lifetimes remains one of the most important challenges of reducing HNSCC morbidity and mortality. To further elucidate the molecular mechanisms, we performed a focused analysis of the genome and immune microenvironment from multiple, matched normal squamous tissue, premalignant lesions, as well as primary and recurrent tumors from seven patients with p16-negative HNSCC. Methods: We performed targeted panel Next Generation Sequencing (161 genes) to analyze somatic variants from sequentially collected, matched formalin-fixed paraffin-embedded tissue (normal, premalignant, HNSCC) from two patients. These samples plus samples from five additional patients were analyzed with the Nanostring PanCancer Immune Panel. In addition, we performed shallow whole genome sequencing (0.5x coverage on average) on samples from three of these patients. Patients were, apart from one case, primarily treated with curative-intent surgery, and received subsequent adjuvant treatment, if indicated. Results: The most frequently mutated genes were TP53 and NOTCH1. Other mutated genes included NOTCH3 and CDKN2A, among others. A significant number of mutations were private to dysplasia and invasive carcinoma, respectively, however, almost 20% were shared between them. Increasing genomic instability was observed when comparing histologically normal squamous mucosa with higher levels of dysplasia. High-grade dysplasia showed similarly rearranged genomes as invasive carcinoma. Pathways related to interferon alpha and gamma response were upregulated even in moderate dysplastic lesions with increasing expression in higher grades of dysplasia and carcinoma. SPINK5, a known tumor suppressor gene in HNSCC, was already downregulated in low-grade dysplastic lesions, indicating an early deactivation in the evolution of the disease. Conclusion: Genomic alterations as well as aberrant immune gene expression can be observed early in the evolution of tumors of the upper aerodigestive tract, highlighting the potential for targeting early mechanisms of disease progression.

RICTOR amplification is associated with Rictor membrane staining and does not correlate with PD-L1 expression in lung squamous cell carcinoma.

RICTOR gene, which encodes the scaffold protein of mTORC2, can be amplified in various tumor types, including squamous cell carcinoma (SCC) of the lung. RICTOR amplification can lead to hyperactivation of mTORC2 and may serve as a targetable genetic alteration, including in lung SCC patients with no PD-L1 expression who are not expected to benefit from immune checkpoint inhibitor therapy. This study aimed to compare RICTOR amplification detected by fluorescence in situ hybridization (FISH) with Rictor and PD-L1 protein expression detected by immunohistochemistry (IHC) in SCC of the lung. The study was complemented by analysis of the publicly available Lung Squamous Cell Carcinoma (TCGA, Firehose legacy) dataset. RICTOR amplification was observed in 20% of our cases and 16% of the lung SCC cases of the TCGA dataset. Rictor and PD-L1 expression was seen in 74% and 44% of the cases, respectively. Rictor IHC showed two staining patterns: membrane staining (16% of the cases) and cytoplasmic staining (58% of the cases). Rictor membrane staining predicted RICTOR amplification as detected by FISH with high specificity (95%) and sensitivity (70%). We did not find any correlation between RICTOR amplification and PD-L1 expression; RICTOR amplification was detected in 18% and 26% of PD-L1 positive and negative cases, respectively. The TCGA dataset analysis showed similar results; RICTOR copy number correlated with Rictor mRNA and protein expression but showed no association with PD-L1 mRNA and protein expression. In conclusion, the correlation between RICTOR amplification and Rictor membrane staining suggests that the latter can potentially be used as a surrogate marker to identify lung SCC cases with RICTOR amplification. Since a significant proportion of PD-L1 negative SCC cases harbor RICTOR amplification, analyzing PD-L1 negative tumors by RICTOR FISH or Rictor IHC can help select patients who may benefit from mTORC2 inhibitor therapy.