Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.

Bevacizumab plays an important role in the first and second line treatment for metastatic colorectal cancer (CRC). And induction of hypoxia and the tumors response to it plays an important role in determining the efficacy of antiangiogenic therapy while the connection between them remains unclear. Here, we found that lactate accumulated in the tumor environment of CRC and acted as substrates for histone lactylation, and this process was further induced by cellular enhanced glycolysis in hypoxia. We determined that CRC patients resistant to bevacizumab treatment presented with elevated levels of histone lactylation and inhibition of histone lactylation efficiently suppressed CRC tumorigenesis, progression and survival in hypoxia. Histone lactylation promoted the transcription of RUBCNL/Pacer, facilitating autophagosome maturation through interacting with BECN1 (beclin 1) and mediating the recruitment and function of the class III phosphatidylinositol 3-kinase complex, which had a crucial role in hypoxic cancer cells proliferation and survival. Moreover, combining inhibition of histone lactylation and macroautophagy/autophagy with bevacizumab treatment demonstrated remarkable treatment efficacy in bevacizumab-resistance patients-derived pre-clinical models. These findings delivered a new exploration and important supplement of metabolic reprogramming-epigenetic regulation, and provided a new strategy for improving clinical efficacy of bevacizumab in CRC by inhibition of histone lactylation.Abbreviations: 2-DG: 2-deoxy-D-glucose; BECN1: beclin 1; CQ: chloroquine; CRC: colorectal cancer; DMOG: dimethyloxalylglycine; H3K18la: histone H3 lysine 18 lactylation; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Nala: sodium lactate; PDO: patient-derived orgnoid; PDX: patient-derived xenograft; RUBCNL/Pacer: rubicon like autophagy enhancer; SQSTM1/p62: sequestosome 1.

Serum levels of n-3 PUFA and colorectal cancer risk in Chinese population.

Circulating n-3 PUFA, which integrate endogenous and exogenous n-3 PUFA, can be better used to investigate the relationship between n-3 PUFA and disease. However, studies examining the associations between circulating n-3 PUFA and colorectal cancer (CRC) risk were limited, and the results remained inconclusive. This case­control study aimed to examine the association between serum n-3 PUFA and CRC risk in Chinese population. A total of 680 CRC cases and 680 sex- and age-matched (5-year interval) controls were included. Fatty acids were assayed by GC. OR and 95 % CI were calculated using multivariable logistic regression after adjustment for potential confounders. Higher level of serum α-linolenic acid (ALA), docosapentaenoic acid (DPA), DHA, long-chain n-3 PUFA and total n-3 PUFA were associated with lower odds of CRC. The adjusted OR and 95 % CI were 0·34 (0·24, 0·49, Pfor trend < 0·001) for ALA, 0·57 (0·40, 0·80, Pfor trend < 0·001) for DPA, 0·48 (0·34, 0·68, Pfor trend < 0·001) for DHA, 0·39 (0·27, 0·56, Pfor trend < 0·001) for long-chain n-3 PUFA and 0·31 (0·22, 0·45, Pfor trend < 0·001) for total n-3 PUFA comparing the highest with the lowest quartile. However, there was no statistically significant association between EPA and odds of CRC. Analysis stratified by sex showed that ALA, DHA, long-chain n-3 PUFA and total n-3 PUFA were inversely associated with odds of CRC in both sexes. This study indicated that serum ALA, DPA, DHA, long-chain n-3 PUFA and total n-3 PUFA were inversely associated with odds of having CRC in Chinese population.

Association between Dietary Fatty Acid Patterns and Colorectal Cancer Risk: A Large-Scale Case-Control Study in China.

Associations of dietary fatty acids with the risk of colorectal cancer (CRC) remain controversial. The objective of this study was to examine whether dietary-derived fatty acid patterns were related to CRC risk among Chinese people. A total of 2806 CRC patients and 2806 frequency-matched controls were interviewed in this case-control study between July 2010 and May 2021. A food frequency questionnaire was used to gather information on dietary intake. Four fatty acid patterns were identified using factor analysis. The even-long-chain fatty acid pattern had no statistically significant association with CRC risk (adjusted Odds ratio (aOR), 1.16; 95% confidence interval (CI), 0.97-1.39; ptrend = 0.129). However, significant inverse associations were found between the medium-chain and long-chain saturated fatty acid (SFA) pattern (aOR, 0.34; 95%CI, 0.27-0.42), the highly unsaturated fatty acid pattern (aOR, 0.73; 95%CI, 0.60-0.88), the odd-chain fatty acid pattern (aOR, 0.69; 95%CI, 0.57-0.83), and CRC risk. The interaction between fatty acid patterns and sex was observed, and the association between the highly unsaturated fatty acid pattern and CRC risk differed by subsite. In conclusion, increasing the intakes of foods rich in medium-chain SFAs, highly unsaturated fatty acids, and odd-chain fatty acids may be related to a lower risk of CRC.

Educational level and colorectal cancer risk: the mediating roles of lifestyle and dietary factors.

OBJECTIVE: The association between the educational level and colorectal cancer risk was controversial in developed countries and evidence was limited in Chinese population. This study aimed to investigate the association between the educational level and colorectal cancer risk in Guangdong Province, China. METHODS: From July 2010 to April 2019, 2502 newly diagnosed colorectal cancer patients and 2538 sex- and age-matched controls were recruited in this case-control study. Multivariable logistic regression models were used to examine the association between the educational level and colorectal cancer risk. Path analysis was used to investigate whether behavioral risk factors potentially mediated the association between the educational level and colorectal cancer risk. RESULTS: Educational level was inversely associated with the colorectal cancer risk. People who graduated from the college or above had a lower risk of colorectal cancer than those from the primary school or below, with an adjusted odds ratio of 0.42 [95% confidence intervals (CI), 0.34-0.52]. The total, direct and indirect effects of the educational level for the colorectal cancer risk were statistically significant in the path diagram. Path analysis showed that lower red and processed meat intake and higher tea and coffee drinking among high educational participants contributed to the inverse association between the educational level and colorectal cancer risk. CONCLUSION: The findings suggested that the educational level was inversely associated with the colorectal cancer risk. The association might be mediated by red and processed meat intake, household and leisure-time activities, and tea and coffee drinking.

Association between Dietary Zinc and Selenium Intake, Oxidative Stress-Related Gene Polymorphism, and Colorectal Cancer Risk in Chinese Population - A Case-Control Study.

Zinc and selenium may protect against colorectal cancer (CRC) progression through their anti-oxidative effects. This study examined the independent and combined effect of dietary zinc and selenium intake, and polymorphisms of the oxidative stress-related genes (superoxide dismutase 1, superoxide dismutase 2, glutathione peroxidase, and catalase) on CRC risk in a Chinese case-control study. A total of 493 cases and 498 sex and age-matched controls were randomly selected from an ongoing case-control study. Dietary information was assessed through face-to-face interviews using a validated food frequency questionnaire. Multiplex PCR-ligase detection reaction was used for genotyping the target SNPs. Multivariable logistic regression was used to estimate the odds ratios (ORs) and 95% confidence interval (CI). Intake of selenium was found to be inversely associated with CRC risk, while zinc was not associated with CRC risk. The ORs (95% CI) for the highest vs. the lowest quartile were 0.42 (95% CI 0.28, 0.64, Ptrend < 0.001) for selenium and 0.96 (95% CI 0.63, 1.47, Ptrend = 0.505) for zinc. Combined effect was observed between zinc and SOD1 rs4998557 on CRC risk (Pinteraction < 0.05). This study identified a novel diet-gene interaction in the oxidative stress pathway on CRC risk in Chinese population.

Voltage-gated sodium channel Nav1.5 promotes tumor progression and enhances chemosensitivity to 5-fluorouracil in colorectal cancer.

Nav1.5, encoded by SCN5A, has been associated with metastasis in colorectal cancer (CRC). Here, we investigated the mechanism by which Nav1.5 regulates tumor progression and whether Nav1.5 influences chemosensitivity to 5-fluorouracil (5-FU) in CRCs. CRC cases were evaluated for Nav1.5 expression. Elevated Nav1.5 expression was associated with poor prognosis in CRCs, whereas stage II/III patients with upregulated SCN5A expression could have better survival after receiving 5-FU-based adjuvant chemotherapy. In CRC cells, SCN5A knockdown reduced the proliferation, migration and invasion. According to RNA sequencing, SCN5A knockdown inhibited both the cell cycle and epithelial-mesenchymal transition. In addition, Nav1.5 stabilized the KRas-calmodulin complex to modulate Ras signaling, promoting Ca2+ influx through the Na+-Ca2+ exchanger and Ca2+ release-activated calcium channel. Meanwhile, SCN5A knockdown increased the 50% inhibitory concentration to 5-FU by upregulating 5-FU-stimulated apoptosis in CRCs. In conclusion, Nav1.5 could progress to proliferation and metastasis through Ca2+/calmodulin-dependent Ras signaling in CRC, and it could also enhance 5-FU-stimulated apoptosis. Clinically, patients with stage II/III CRCs with elevated SCN5A expression demonstrated poor prognosis, yet those patients could benefit more from 5-FU-based chemotherapy than patients with lower SCN5A expression.

Association between phytosterol intake and colorectal cancer risk: a case-control study.

A study in rodent models showed that phytosterols protected against colon carcinogenesis, probably by inhibiting dysregulated cell cycle progression and inducing cellular apoptosis. However, epidemiological studies on the relationship between phytosterols and colorectal cancer risk are quite limited. The aim of this study was to investigate dietary phytosterol intake in relation to colorectal cancer risk in the Chinese population. A case-control study was conducted from July 2010 to June 2016, recruiting 1802 eligible colorectal cancer cases plus 1813 age (5-year interval) and sex frequency-matched controls. Dietary information was collected by using a validated FFQ. The OR and 95 % CI of colorectal cancer risk were assessed by multivariable logistic regression models. A higher total intake of phytosterols was found to be associated with a 50 % reduction in colorectal cancer risk. After adjusting for various confounders, the OR of the highest quartile intake compared with the lowest quartile intake was 0·50 (95 % CI 0·41, 0·61, P trend<0·01) for total phytosterols. An inverse association was also found between the consumption of ß-sitosterol, campesterol, campestanol and colorectal cancer risk. However, stigmasterol intake was related to an increased risk of colorectal cancer. No statistically significant association was found between ß-sitostanol and colorectal cancer risk. Stratified analysis by sex showed that the positive association of stigmasterol intake with colorectal cancer risk was found only in women. These data indicated that the consumption of total phytosterols, ß-sitosterol, campesterol and campestanol is inversely associated with colorectal cancer risk in a Chinese population.

Flavonoid intake from vegetables and fruits is inversely associated with colorectal cancer risk: a case-control study in China.

Flavonoids may play an important role in the protective effects of vegetables, fruits and tea against colorectal cancer. However, associations between flavonoids and colorectal cancer risk are inconsistent, and a few studies have evaluated the effect of flavonoids from different dietary sources separately. This study aimed to evaluate associations of flavonoids intake from different dietary sources with colorectal cancer risk in a Chinese population. From July 2010 to December 2015, 1632 eligible colorectal cancer cases and 1632 frequency-matched controls (age and sex) completed in-person interviews. A validated FFQ was used to estimate dietary flavonoids intake. Multivariate logistical regression models were used to calculate the OR and 95 % CI of colorectal cancer risk after adjusting for various confounders. No significant association was found between total flavonoids and colorectal cancer risk, with an adjusted OR of 1·06 (95 % CI 0·85, 1·32) comparing the highest with the lowest quartile. Anthocyanidins, flavanones and flavones intakes from total diet were found to be inversely associated with colorectal cancer risk. Compared with the lowest quartile, the adjusted OR for the highest quartile were 0·80 (95 % CI 0·64, 1·00) for anthocyanidins, 0·28 (95 % CI 0·22, 0·36) for flavanones and 0·54 (95 % CI 0·43, 0·67) for flavones. All subclasses of flavonoids from vegetables and fruits were inversely associated with colorectal cancer. However, no significant association was found between tea flavonoids and colorectal cancer risk. These data indicate that specific flavonoids, specifically flavonoids from vegetables and fruits, may be linked with the reduced risk of colorectal cancer.

Efficacy, compliance and reasons for refusal of postoperative chemotherapy for elderly patients with colorectal cancer: a retrospective chart review and telephone patient questionnaire.

BACKGROUND: Numerous clinical trials have demonstrated that elderly patients with colorectal cancer (CRC) can benefit from chemotherapy, yet compliance in real-world practice is low. The purpose of this study is to investigate the efficacy, compliance and reasons for refusal of postoperative chemotherapy for elderly patients with CRC and to provide corresponding strategies. PATIENTS AND METHODS: The clinico-pathological and biochemical data of the chemotherapy group and chemo-refusing group were compared among 386 elderly patients (>70 years old) with CRC who underwent surgery. 226 patients received chemotherapy and 160 patients refused. Follow-up of the subjective reasons for refusal was investigated using the elderly caner patients' chemo-refusal reason questionnaire (ECPCRRQ) prepared by the authors and a group of psychologists. The questionnaire is administrated by telephone. A predictive model for 5-year disease-free survival (DFS) and 5-year overall survival (OS) was constructed by using Kaplan-Meier analysis, logistic and Cox regression. RESULTS: Among stage III patients, receiving chemotherapy was associated with a significantly higher OS (68%) compared to those who refused ( OS 50%) (HR: 2.05, 95%CI: 1.12-3.77, P = 0.02). The Chemo-refusal group had more female and elderly patients, significantly higher rate of severe complications, and lower body mass index (BMI). Follow-up phone questionnaire analysis showed the doctors' uncertainty of chemotherapy benefit, economic difficulties, uncomfortable feeling, superstition of Traditional Chinese Medicine, concealing information and lack of social support were the main factors for elderly CRC patients to decline chemotherapy. CONCLUSION: The receipt of post-operative chemotherapy in elderly patients with resected stage III CRC was associated with a more favorable survival. The low compliance rate (160/386) of postoperative chemotherapy was influenced by various subjective and objective factors.