Targeting anoikis resistance as a strategy for cancer therapy.

Anoikis, known as matrix detachment-induced apoptosis or detachment-induced cell death, is crucial for tissue development and homeostasis. Cancer cells develop means to evade anoikis, e.g. anoikis resistance, thereby allowing for cells to survive under anchorage-independent conditions. Uncovering the mechanisms of anoikis resistance will provide details about cancer metastasis, and potential strategies against cancer cell dissemination and metastasis. Here, we summarize the principal elements and core molecular mechanisms of anoikis and anoikis resistance. We discuss the latest progress of how anoikis and anoikis resistance are regulated in cancers. Furthermore, we summarize emerging data on selective compounds and nanomedicines, explaining how inhibiting anoikis resistance can serve as a meaningful treatment modality against cancers. Finally, we discuss the key limitations of this therapeutic paradigm and possible strategies to overcome them. In this review, we suggest that pharmacological modulation of anoikis and anoikis resistance by bioactive compounds could surmount anoikis resistance, highlighting a promising therapeutic regimen that could be used to overcome anoikis resistance in cancers.

Multidrug resistance transporters P-gp and BCRP limit the efficacy of ATR inhibitor ceralasertib in cancer cells.

The therapeutic effect of chemotherapy and targeted therapy are known to be limited by drug resistance. Substantial evidence has shown that ATP-binding cassette (ABC) transporters P-gp and BCRP are significant contributors to multidrug resistance (MDR) in cancer cells. In this study, we demonstrated that a clinical-staged ATR inhibitor ceralasertib is susceptible to P-gp and BCRP-mediated MDR. The drug resistant cancer cells were less sensitive to ceralasertib compared to the parental cells. Moreover, ceralasertib resistance can be reversed by inhibiting the drug efflux activity of P-gp and BCRP. Interestingly, ceralasertib was able to downregulate the level of P-gp but not BCRP, suggesting a potential regulation between ATR signaling and P-gp expression. Furthermore, computational docking analysis predicted high affinities between ceralasertib and the drug-binding sites of P-gp and BCRP. In summary, overexpression of P-gp and BCRP are sufficient to confer cancer cells resistance to ceralasertib, underscoring their role as biomarkers for therapeutic efficacy.

Neoadjuvant chemoimmunotherapy shows major pathological response and low recurrence in head and neck squamous cell carcinoma.

BACKGROUND: The study aimed to investigate the efficacy and survival outcomes of neoadjuvant chemotherapy combined with programmed cell death protein 1 (PD-1) blockade (neoadjuvant chemoimmunotherapy) for patients with resectable head and neck squamous cell carcinoma (HNSCC). METHODS: A retrospective analysis was conducted. Patients with initially diagnosed, resectable HNSCCs who received the neoadjuvant chemoimmunotherapy and radical surgery were included. Correlation analysis between patients' clinical characteristics and pathological responses, and survival analysis were performed. RESULTS: A total of 79 patients were included. The majority of patients (55, 69.6%) were diagnosed at locally advanced stages and most of them (58, 73.4%) had tumor located at the oral cavity. Nearly half of patients (35, 44.3%) received two cycles of neoadjuvant chemoimmunotherapy and the rest had three or more cycles. The R0 resection rate was 98.7%. In the pathological evaluation, 53.1% of patients reached pathological complete responses or major pathological responses. After a median follow-up of 17.0 months, the 1-year disease-free survival (DFS) and overall survival (OS) rates were 87.2% and 97.4%, respectively. The pathological response showed a significantly positive association with survival benefits (p < 0.001). Patients with human papillomavirus (HPV)-positive oropharyngeal cancer had the best pathological response and survival outcomes. Besides, history of radiation at head and neck region and poor pathological response were found to be independent risk factors of DFS for patients receiving such treatments. CONCLUSION: Neoadjuvant chemoimmunotherapy of HNSCC showed high rate of pathological response and low recurrence rate, holding promise for becoming the new standard of care for resectable HNSCC.

FSCN1 promotes proliferation, invasion and glycolysis via the IRF4/AKT signaling pathway in oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a disease with increasing incidence worldwide that leads to deformity and death. In OSCC, fascin actin-bundling protein 1 (FSCN1) is an oncogene involved in the tumorigenesis process. However, the functions and potential mechanisms of FSCN1 in the OSCC tumorigenesis process have not been reported thus far. METHODS: We used qRT‒PCR to detect the expression of FSCN1 in 40 paired OSCC tumor tissues (tumor) and neighboring noncancerous tissues. The role of FSCN1 was also assessed in vitro through colony formation, CCK-8, and transwell assays. Moreover, glucose consumption was detected. Western blotting was used to confirm the interaction of FSCN1, IRF4 and AKT. RESULTS: FSCN1 was remarkably overexpressed in OSCC tissues and cell lines compared to corresponding controls. In addition, colony formation, CCK-8, and transwell assays revealed a notable reduction in OSCC growth and invasion when FSCN1 was silenced. FSCN1 silencing remarkably suppressed OSCC glycolysis. Mechanistic studies showed that FSCN1 achieves its function partially by activating interferon regulatory factor 4 (IRF4) and the AKT pathway in OSCC. CONCLUSION: In conclusion, our study investigated the functions and mechanisms of the FSCN1/IRF4/AKT pathway in OSCC progression. In OSCC, FSCN1 is likely to be a biomarker and therapeutic target.

Treatment outcomes of mucosal melanoma of the head and neck: Analysis of 190 cases from a single institution.

Objectives: To analyze the treatment outcomes and prognostic factors of mucosal melanoma of the head and neck (MMHN) from a single institution. Methods: From December 1989 to November 2018, 190 patients diagnosed with MMHN were included. Survival analysis was performed using the Kaplan-Meier method for univariate analysis with a log-rank test for significance and Cox regression for multivariate analysis. Results: With a median follow-up time of 43.5 months, 126 (68.5%) patients died. The median DSS was 35 months. The 3- and 5-year disease-specific survival (DSS) rates were 48.1% and 33.7%, respectively. The median overall survival (OS) was 34 months. The 3- and 5-year OS rates were 47.0% and 32.9%, respectively. In univariate analysis, the T3 stage, received surgery, R0 resection, and combined therapy (surgery+biotherapy/biochemotherapy) were significantly associated with better survival. Multivariable Cox regression analysis revealed that the T4 stage (HR = 1.692; 95% CI, 1.175-2.438; p = .005) and the N1 stage (HR = 1.600; 95% CI, 1.023-2.504; p = .039) were strong prognostic factors for poor survival, and that combined therapy (surgery+biotherapy/biochemotherapy) was a strong prognostic factor for better survival outcome (HR = 0.563; 95% CI, 0.354-0.896; p = .015). Conclusion: The prognosis of MMHN remains poor. Systemic treatment is warranted to reduce MMHN progression. Surgery combined with biotherapy may improve survival.

The Prognostic Significance of FOXD1 Expression in Head and Neck Squamous Cell Carcinoma.

It has been reported that forkhead box D1 (FOXD1) plays an established role in human early embryonic development and is broadly involved in various malignancies. However, there is limited information regarding FOXD1 expression in head and neck squamous cell carcinoma (HNSCC). This present study aimed to explore the clinical significance of FOXD1 in patients with HNSCC. Tissue microarrays of 334 primary HNSCC patients who underwent surgery between 2008 and 2010 at Sun Yat-sen University Cancer Center were investigated by immunohistochemistry regarding FOXD1 expression. χ2 test was used to estimate the relationship of FOXD1 expression with clinicopathologic characteristics. Univariate and multivariate analyses were performed to identify FOXD1 expression as an independent prognostic indicator of overall survival (OS) and disease-free survival (DFS). FOXD1 expression is closely associated with postoperative recurrence. HNSCC patients with high FOXD1 expression have poorer prognoses than the low-expression group (p < 0.05). According to multivariate analysis, FOXD1 was an independent prognostic factor for OS and DFS. The results revealed that FOXD1 could be a prognostic factor for HNSCC and might serve as a potential target for novel therapies.

Analysis of T1-T2 stage oropharyngeal squamous cell carcinoma treated with transoral robotic surgery.

Objective: Transoral robotic surgery (TORS) has become an effective treatment for early-stage oropharyngeal squamous cell carcinomas (OPSCCs). We aimed to analyze the clinical safety and efficacy of TORS for human papilloma virus (HPV)-positive and HPV-negative OPSCC in China. Methods: Patients with OPSCC of pT1-T2 stage who underwent TORS from March 2017 to December 2021 were analyzed. Results: A total of 83 patients (HPV-positive, n = 25; HPV-negative, n = 58) were included. The median age of the patients was 57.0 years and 71 were men. The majority of primary tumor sites were palatine tonsils (52, 62.7%) and base of tongues (20, 24.1%). Three patients have a positive margin. A total of 12 (14.5%) patients received tracheotomies, the average duration of tracheostomy tube use was 9.4 days, and nasogastric tube was 14.5 days. No patient had a long-term tracheotomy. The 3-year overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS) for all 83 patients were 89.5%, 80.1%, and 83.3%, respectively. The OS at 3 years between the HPV-positive group and HPV-negative group were 100% versus 84.3% (P = .07), while the DFS and RFS between two groups also showed no significant difference. Among multivariate cox regression analysis of all potential risk factors, smoking was the significant risk factors for disease recurrence (P < .05). Conclusion: Transoral robotic surgery achieved encouraging oncologic outcomes and safety in T1-T2 stage OPSCC treatment, regardless of HPV status. Level of Evidence: 4.

Short-Term Efficacy of the Transnasal-Transoral Approach to Endoscopic Nasopharyngectomy for Nasopharyngeal Adenocarcinoma.

OBJECTIVES: Nasopharyngeal adenocarcinomas (NPACs) are rare malignant tumors. The treatment of NPACs is usually surgery with resection of normal nasal passage tissues.We introduced an innovative double endoscopic surgery for NPACs patients and evaluated the clinical efficacy of this approach. METHODS: The clinical data of 4 NPACs patients who underwent radical endoscopic nasopharyngectomy using a combined transnasal and transoral approach were analyzed to determine the efficacy of this surgery. The endpoints were en bloc resection and relief of clinical symptoms. RESULTS: All surgeries were successfully performed without any severe postoperative complications or death. Postoperative MRI revealed that en bloc resection was achieved for all patients with NPACs, and they had high quality of life without postoperative complications. CONCLUSIONS: The transnasal-transoral approach to endoscopic nasopharyngectomy for nasopharyngeal adenocarcinoma is safe and effective.

Postoperative radiotherapy to the neck for pN1 status HNSCC patients after neck dissection.

The significance of postoperative radiotherapy (PORT) to the neck for pN1 status head and neck squamous cell carcinomas (HNSCC) after neck dissection is unclear. A total of 208 patients with pN1 status HNSCC treated from January 1, 2001, to December 31, 2014, were enrolled in the current study. The 5-year regional recurrence-free survival (RRFS), overall survival (OS) and distant metastasis-free survival (DMFS) were compared between patients with or without PORT to the dissected neck. Moreover, the stratified Cox proportional hazards models were used to assess the association between PORT to the neck and survival before and after propensity score matching. Seventy-nine patients received PORT to the neck, while 129 did not. All patients were followed for over 5 years, with a median follow-up duration of 64.6 months. The PORT group did not show better survival results than the group without PORT to the neck in RRFS, OS or DMFS. Moreover, no evidence showed that PORT to the neck was independently associated with 5-year survival. PORT to the neck for pN1 status HNSCC after neck dissection did not lead to better survival. However, it is necessary to conduct prospective randomized clinical trials to confirm these results.

Research on the Effect of Authenticity on Revisit Intention in Heritage Tourism.

The authenticity of heritage tourism is an important factor for attracting tourists. Research has shown that authenticity is related to revisit intention. However, little attention has been paid to the impact of heritage tourism authenticity on revisit intention. Drawing on cognitive appraisal theory, we constructed a model of the mechanism underlying this relationship. Questionnaires were distributed at one world heritage site (the Dujiangyan irrigation system) in China, and data from 596 valid cases were collected. Using structural equation modeling, the results showed that authenticity, directly and indirectly, affects tourists' revisit intention via memorable tourism experiences and place attachment. The current paper enriches existing literature on the relationship between authenticity and revisit intention and provides a theoretical basis for promoting authenticity and revisit intention in heritage tourism.

Retraction Notice to: Upregulation of OIP5-AS1 Predicts Poor Prognosis and Contributes to Thyroid Cancer Cell Proliferation and Migration.

[This retracts the article DOI: 10.1016/j.omtn.2019.11.036.].

Corrigendum: Lateral Lymph Node Metastases in T1a Papillary Thyroid Carcinoma: Stratification by Tumor Location and Size.

[This corrects the article DOI: 10.3389/fendo.2021.716082.].

Upregulated circRAD18 promotes tumor progression by reprogramming glucose metabolism in papillary thyroid cancer.

BACKGROUND: By regulating complex functional processes, circRNAs are crucial in the development of different cancers. Nevertheless, most circRNAs in papillary thyroid cancer metabolic reprogramming remain unknown. METHODS: The expression of circRNA was assessed by qRT-PCR in papillary thyroid cancer tissues and cell lines. Cell proliferation and glucose intake experiments were performed by certain kit. Transwell assays and wound healing assays were performed to investigate the function of circRNA in metastasis. In addition, a serious of molecular experiments were conducted to determine the exact mechanism of circRAD18. Luciferase reporter and RNA immunoprecipitation assay were conducted to determine the molecular interaction between circRNA and miRNA. RESULTS: We characterized circRAD18 as a significantly upregulated circRNA in papillary thyroid tissues and cell lines and found its downregulation could inhibit the growth and metastasis ability of papillary thyroid cancer. Interestingly, we found that circRAD18 was involved in glucose metabolism reprogramming of papillary thyroid cancer, and its silence could remarkably inhibit cell glucose uptake and lactate production in papillary thyroid cancer cells. Inhibition of circRAD18 could decrease the expression level of PDK1 protein by sponging miR-516b. CONCLUSIONS: This study verified the novel function of the circRAD18-miR-516b-PDK1 axis in papillary thyroid cancer metabolic reprogramming progression, which has potential to be a novel therapeutic target.

The Effects of COVID-19 Risk Perception on Travel Intention: Evidence From Chinese Travelers.

This study attempts to assess the relationship between risk perception, risk knowledge, and travel intentions of Chinese leisure travelers during the COVID-19 pandemic in the framework of social contagion and risk communication theories by analyzing a sample of 1,209 travelers through structural equation modeling (SEM) and path analysis. We used the process macro of Hayes to analyze the moderation effects of age, gender, and education between risk perception, media and interpersonal communication, and risk knowledge. It was found that travelers were more concerned about self-efficacy than severity. Risk perception of travelers predicts the information-seeking process of tourists. This process helps travelers to accumulate risk information that influences their travel intentions. Travelers give more importance to interpersonal (contagion) communication in making a traveling decision. Demographic factors influence traveling decision-making; women travelers were found to be more risk resilient than men. Young travelers seek information at low- and old travelers at high-risk levels. Marketing implications also provided.

Lateral Lymph Node Metastases in T1a Papillary Thyroid Carcinoma: Stratification by Tumor Location and Size.

Objective: To analyze the incidence and risk factors for lateral lymph node metastases (LNMs) in T1a papillary thyroid carcinoma (PTC) with a focus on tumor location and size. Materials and Methods: The incidence of lateral LNM in 345 cases of T1a PTC was retrospectively analyzed. Univariate and multivariate analyses were performed to assess the relationships between lateral LNM and clinicopathological characteristics. Results: The incidence of skip metastasis to lateral LNM in T1a PTC located in the upper lobe was 12.1% (8/66). Logistic regression analysis indicated tumor size >5 mm (OR = 5.04, 95% CI = 1.79 to 14.18, P = 0.002), upper lobe location (OR = 7.68, 95% CI = 3.05-19.34, P < 0.001) and the number of central neck LNM (<2: OR = 24.79, 95% CI = 8.23-74.60, P < 0.001; ≥2: OR = 4.99, 95% CI = 1.95-12.73, P < 0.001) were independently associated with lateral LNM. Comparing the lateral and central LNM stratification based on tumor location revealed that both the incidences of lateral (33.3%) and central (30.3%) LNM of T1a PTC located in the upper lobe were higher than those of T1a PTC located in the middle and lower lobes. Of T1a PTC located in the upper lobe, the incidence of lateral LNM was 33.3% (22/66), which was higher than that [30.3% (20/66)] of central LNM. This finding is reversed in all T1a PTC cases and T1a PTC cases with tumor located in the middle and lower lobes. Conclusion: A particularly high likelihood of lateral LNM was observed in T1a PTC patients with tumor located in the upper lobe of the thyroid gland, especially the tumor >5 mm in size, which could be considered a risk factor for lateral LNM in the clinical management of T1a PTC.

Performance of cropland low-carbon use in China: Measurement, spatiotemporal characteristics, and driving factors.

Low-carbon cropland use is of significant importance in addressing global warming. Most research has paid attention to measuring cropland use efficiency under carbon emission constraints to reconcile carbon mitigation and food security. However, there are limitations with carbon accounting, approach selection, and subsequent regression. To extend existing research, this study aimed to evaluate the performance of cropland low-carbon use (PCLU) and determine the driving factors. In this study, carbon emissions and sequestration of cropland use in Chinese provinces from 2000 to 2019 were calculated. Based on the carbon accounting, an extended slack-based efficiency measurement was applied to evaluate the provincial PCLU. Besides, spatiotemporal characteristics of the PCLU were portrayed. Owing to spatial correlation, the spatial Durbin model was employed to elucidate the driving factors. The results indicate that: (1) cropland use systems acted as net carbon sinks in China with sequestration and emissions of 5.624 t/hm2 and 1.980 t/hm2, respectively. (2) In China, the average PCLU was 0.727, whereas the provinces had values ranging from 0.2-1.2, with significant gaps. (3) PCLU evolved stably in northeastern China and fluctuated in the other three regions. Meanwhile, provinces with high PCLU shifted from the south to the north of the country during the study period. The global Moran's index demonstrated that a positive spatial correlation existed. (4) Agricultural structure adjustment and urbanization can promote PCLU, whereas investment and disaster can undermine it. PCLU of a province would be affected by the agricultural structure and disaster in its nearby provinces owing to spillover effects. Consequently, it is suggested that emissions in provinces should be mitigated according to the local carbon structure. Harnessing the key factors and spatial interactions can potentially help achieve regional low-carbon cropland use.

Circular RNA circKIF4A facilitates the malignant progression and suppresses ferroptosis by sponging miR-1231 and upregulating GPX4 in papillary thyroid cancer.

Circular RNAs (circRNAs) are one type of non-coding RNA. They act as important role in regulating various biological processes in the malignant progression. But we don't clearly know the specific mechanism of the majority circRNAs in papillary thyroid tumor progression. In the current study, we explored circKIF4A and the result showed that it had high expression in papillary thyroid cancer. The functions of circKIF4A were explored by CCK-8, transwell, and mouse xenograft experiments. Knockdown of circKIF4A could suppress papillary thyroid cell growth and migration. In addition, RIP assays and dual luciferase vector reporter assays were further conducted. Our consequence showed circKIF4A facilitated the malignant progress of papillary thyroid tumor by sponging miR-1231 and upregulating GPX4 expression. In conclusion, our study proved that circKIF4A-miR-1231-GPX4 axis played a vital role in cancer proliferation and ferroptosis by competing endogenous RNAs. Therefore, targeting circKIF4A is very likely to be a potential method for treatment of papillary thyroid cancer in the future.

High SOX8 expression promotes tumor growth and predicts poor prognosis through GOLPH3 signaling in tongue squamous cell carcinoma.

According to our previous study, GOLPH3 is markedly up-expressed in tongue squamous cell carcinoma (TSCC), which is also associated with poor survival. However, it remains unclear about key upstream and downstream mechanisms of GOLPH3. This study aimed to illuminate new mechanisms modulating GOLPH3 upregulation and promoting TSCC development at the molecular level. Using mass spectrometry and agarose-streptavidin-biotin pull-down analyses, SOX8 (SRY-Box 8) was identified to be the new protein to bind the GOLPH3 promoter within TSCC cells, which was further verified to be the regulator of GOLPH3 upregulation. The knockdown of SOX8 suppressed the promoter activity of GOLPH3, while secondarily inhibiting TSCC cell proliferation both in vivo and in vitro. Interestingly, GOLPH3 overexpression rescued the SOX8 knockdown-mediated suppression on TSCC proliferation. Additionally, exogenous over-expression of SOX8 also activated the activity of promoter as well as GOLPH3 expression, in the meantime of promoting TSCC development. Moreover it was discovered that SOX8 regulated GOLPH3 expression through interacting with TFAP2A. Moreover our results suggested that the SOX8 level was increased within tumor tissue compared with that in para-cancer normal counterpart, which showed positive correlation with the GOLPH3 level. According to Kaplan-Meier analyses, TSCC cases having higher SOX8 and GOLPH3 expression were associated with poorer prognostic outcomes. Taken together, this study reveals that SOX8 enhances the TSCC cell growth via the direct transcriptional activation of GOLPH3, which also indicates the potential to use SOX8/GOLPH3 pathway as the treatment target among TSCC patients.

Older age is a risk factor associated with poor prognosis of patients with squamous cell carcinoma of the oral cavity.

PURPOSE: Whether or not young patients with squamous cell carcinoma of oral cavity (OC-SCC) have a difference in prognosis remains a controversy. This study aimed to analyze the clinical characteristics and difference of survival rates between adult patients less than 40 years of age and those 40 years of age and older. METHODS: A retrospective analysis was conducted using the database of patients diagnosed with OC-SCC between 1990 and 2013 in the Sun Yat-sen University Cancer Center, but patients older than 85 years, younger than 18 years, or died within 6 months of diagnosis were excluded. Patients were categorized into two groups: the young group (< 40 years of age) and the older group (≥ 40 years of age). Cox regression, survival and subgroups analyses were performed. The primary endpoints included the rates of 5-year overall survival (OS) and disease-specific survival (DSS). RESULTS: A total of 1902 OC-SCC patients were identified. The percentage of female in the young group was significantly higher than that in the older group (40.27% vs 31.03%, p < 0.001). This study failed to find the difference in TNM classification or tumor stage between the two groups (p > 0.05). The young group was more likely to receive adjuvant radiotherapy and/or chemotherapy (42.48% vs 26.91%, p < 0.001). The 5-year OS rate (71% vs. 57%, p < 0.001) and DSS rate (72% vs 58%, p < 0.001) in patients under 40 years were significantly higher than those for the older group. CONCLUSION: Our findings suggested that OC-SCC in younger patients did not present at a more advanced stage. In addition, young age is an independent predictor for better survival.

Upregulation of OIP5-AS1 Predicts Poor Prognosis and Contributes to Thyroid Cancer Cell Proliferation and Migration.

As a common malignancy, thyroid cancer mainly occurs in the endocrine system. There have been accumulating studies on therapeutic methods of thyroid cancer, but its internal molecular mechanism is still not fully understood. Long noncoding RNA (lncRNA) OIP5-AS1 was confirmed as an oncogene and related to poor prognosis in various cancers. Nevertheless, its role and underlying mechanism remain unclear in thyroid cancer. Here, we observed a significant upregulation of OIP5-AS1 in thyroid cancer tissues and cells, and upregulated OIP5-AS1 was correlated with poor prognosis in thyroid cancer. Moreover, OIP5-AS1 knockdown resulted in the inhibited cell proliferation and migration, while overexpressed OIP5-AS1 exhibited the reverse function in thyroid cancer. Besides, OIP5-AS1 was found to positively regulate Wnt/ß-catenin signaling pathway. Through mechanism exploration, OIP5-AS1 was discovered to activate Wnt/ß-catenin signaling pathway via FXR1/YY1/CTNNB1 axis. Finally, rescue assays indicated that the inhibitive role of silenced OIP5-AS1 in thyroid cancer cell growth and Wnt/ß-catenin signaling pathway could be rescued by overexpression of CTNNB1 or addition of lithium chloride (LiCl). In conclusion, upregulation of OIP5-AS1 predicted unfavorable prognosis and enhanced thyroid cancer cell growth by activating Wnt/ß-catenin signaling pathway.