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Background Circular RNAs (circRNAs) have gained attention as novel biomarkers for cancer diagnosis and prognosis. Aberrant expression of circRNAs is widely involved in cancer development, whereas the function and mechanism of novel circRNAs in colorectal cancer (CRC) remain unclear. Methods CircZFR was identified both in CRC tissues from the GEO database and in serum exosomes by competing endogenous RNA (ceRNA) microarray. The expression of circZFR was evaluated in CRC tissues and serum by qRT-PCR and in tissue microarray (TMA) by FISH. The functional roles were confirmed using a series of in vitro assays and tumor xenografts and pulmonary/hepatic metastasis mouse models. The mechanisms of circZFR were assessed through circRNA pulldown, RNA immunoprecipitation (RIP), dual-luciferase reporter assays and rescue experiments. Lastly, TCP1-CD-QDs nanocarrier was used to carry circZFR siRNA (si-circZFR) to exam the therapeutic potential of circZFR in patient-derived xenograft (PDX) models. Results CircZFR was upregulated in cancer tissues and serum exosomes of CRC patients and its level was positively associated to advanced TNM stages and poor prognosis. Serum circZFR was indicative of CRC incidence, advanced-stages and metastasis. Functional experiments demonstrated that circZFR promoted CRC proliferation and metastasis but inhibited apoptosis in vitro and in vivo, exosomes with upregulation of circZFR facilitated growth and migration of cocultured CRC cells. Mechanistically, the generation of circZFR could be improved by epithelial splicing regulatory protein 1 (ESRP1) in CRC cells. CircZFR bound to BCL2-associated transcription factor 1 (BCLAF1) and inhibited its ubiquitinated degradation. Moreover, circZFR sponged miR-3127-5p to increase the expression of rhotekin 2 (RTKN2). Our TCP1-CD-QDs nanocarrier was able to carry si-circZFR and delivered them to the vasculature of CRC tissues and cells, resulting in suppressive tumor growth without obvious adverse effects in PDX models. Conclusions Our findings indicate that ESRP1-mediated circZFR exerts oncogenic effects on CRC development and spread through suppressing BCLAF1 degradation and regulating the miR-3127-5P/RTKN2 axis. CircZFR is a promising serum biopsy marker for CRC diagnosis and an attractive target for further therapy. more...

Background: Tumor metastasis of colorectal cancer (CRC) is the main cause of death in most patients and the major difficulty in comprehensive CRC treatment. Circular RNAs (circRNAs) affect many biological functions in solid tumors. However, their mechanisms in CRC metastasis remain unclear. Methods: RNA sequencing (RNA-seq) and quantitative real-time PCR were performed to screen differentially expressed circRNAs between CRC tissues and adjacent normal tissues. CCK-8, cell migration and wound healing assays were performed to determine the functions of circRHOBTB3 in cell proliferation and metastasis. RNA pulldown and RNA immunoprecipitation assays were performed to verify the interaction between circRHOBTB3 and the HuR (ELAVL1) protein. Further RNA-seq and rescue experiments were applied to search for the downstream target. We also conducted a mouse xenograft model to elucidate the effect of circRHOBTB3 on cancer metastasis in vivo. Results: We identified circRHOBTB3 which is markedly downregulated in CRC tissues and cell lines. Furthermore, lower circRHOBTB3 levels were significantly associated with advanced clinical stages and greater risk of metastases. Overexpression of circRHOBTB3 suppresses tumor metastasis in CRC cells. Mechanistically, circRHOBTB3 binds to HuR, which is a ubiquitously expressed and functional RNA-binding protein (RBP) in CRC development, and promotes β-Trcp1-mediated ubiquitination of HuR. Normally, HuR binds to the 3'UTR of target mRNAs to facilitate their stabilization, whereas the interaction between circRHOBTB3 and HuR degrades HuR to reduce the expression level of the downstream target PTBP1. Furthermore, overexpressed circRHOBTB3 suppresses lung metastases in vivo, and this effect can be partly reversed by PTBP1 overexpression. In addition, the transcription of circRHOBTB3 can be improved by both FUS and ADARB2 in CRC cells. Conclusions: Our findings indicate that circRHOBTB3 exerts suppressive effects on CRC aggressiveness through the HuR/PTBP1 axis. more...

Background Oridonin has been demonstrated to exert strong antitumor activities in various types of human cancers. Our previous study established that oridonin induced the apoptosis of and exerted an inhibitory effect on colon cancer cells in vitro and in vivo. However, the mechanisms behind the antitumor effects of oridonin on colorectal cancer are not clearly known. This study explored whether autophagy was involved in antitumorigenesis effects caused by the usage of oridonin in colon cancer and examined whether the AMPK/mTOR/ULK1 signaling pathway was involved in this process. Methods Cell viability was determined using CCK-8 assay. The distribution of cell apoptosis was evaluated using flow cytometry. RT-PCR and Western blotting analysis were conducted to identify the key target genes and proteins involved in the AMPK/mTOR cascade. AMPK siRNA was used to disturb AMPK expression. A DLD-1 cell orthotopic transplantation tumor model was established to explore the anti-cancer effects in vivo. Results Oridonin exhibited a suppressive effect on DLD-1 cells in a concentration- and time-dependent manner. Additionally, in a dose-dependent manner, oridonin induced cell apoptosis via inducing the protein expression levels of cleaved caspase-3, cleaved PARP and stimulated autophagy by increasing protein expression levels of Becin1, LC3-II, decreasing protein expression levels of LC3-I, p62, which were respectively attenuated and elevated by autophagy inhibitor 3-MA. Furthermore, oridonin upregulated the expression level of p-AMPK and downregulated the expression levels of p-mTOR, p-ULK1 in the DLD-1 cells in a dose-dependent manner. Moreover, knockdown of AMPK by a specific siRNA reversed the expression levels of proteins involved in the AMPK/mTOR pathway, autophagy and apoptosis. In addition, outcomes from the in vivo experiments also showed that oridonin treatment significantly repressed tumorigenic growth of DLD-1 cells without any side effects, which was accompanied by the upregulation of p-AMPK, LC3-II, active caspase-3 protein expression levels and the downregulation of p-mTOR and p-ULK1 protein expression levels. Conclusion This study demonstrated that oridonin induced apoptosis and autophagy of colon cancer DLD-1 cells via regulating the AMPK/mTOR/ULK1 pathway, which indicated that oridonin may be used as a novel therapeutic intervention for patients with colorectal cancer. more...

Background Circular RNAs (circRNAs) have gained attention as novel biomarkers for cancer diagnosis and prognosis. Aberrant expression of circRNAs is widely involved in cancer development, whereas the function and mechanism of novel circRNAs in colorectal cancer (CRC) remain unclear. Methods CircZFR was identified both in CRC tissues from the GEO database and in serum exosomes by competing endogenous RNA (ceRNA) microarray. The expression of circZFR was evaluated in CRC tissues and serum by qRT-PCR and in tissue microarray (TMA) by FISH. The functional roles were confirmed using a series of in vitro assays and tumor xenografts and pulmonary/hepatic metastasis mouse models. The mechanisms of circZFR were assessed through circRNA pulldown, RNA immunoprecipitation (RIP), dual-luciferase reporter assays and rescue experiments. Lastly, TCP1-CD-QDs nanocarrier was used to carry circZFR siRNA (si-circZFR) to exam the therapeutic potential of circZFR in patient-derived xenograft (PDX) models. Results CircZFR was upregulated in cancer tissues and serum exosomes of CRC patients and its level was positively associated to advanced TNM stages and poor prognosis. Serum circZFR was indicative of CRC incidence, advanced-stages and metastasis. Functional experiments demonstrated that circZFR promoted CRC proliferation and metastasis but inhibited apoptosis in vitro and in vivo, exosomes with upregulation of circZFR facilitated growth and migration of cocultured CRC cells. Mechanistically, the generation of circZFR could be improved by epithelial splicing regulatory protein 1 (ESRP1) in CRC cells. CircZFR bound to BCL2-associated transcription factor 1 (BCLAF1) and inhibited its ubiquitinated degradation. Moreover, circZFR sponged miR-3127-5p to increase the expression of rhotekin 2 (RTKN2). Our TCP1-CD-QDs nanocarrier was able to carry si-circZFR and delivered them to the vasculature of CRC tissues and cells, resulting in suppressive tumor growth without obvious adverse effects in PDX models. Conclusions Our findings indicate that ESRP1-mediated circZFR exerts oncogenic effects on CRC development and spread through suppressing BCLAF1 degradation and regulating the miR-3127-5P/RTKN2 axis. CircZFR is a promising serum biopsy marker for CRC diagnosis and an attractive target for further therapy. more...

Anastomotic stenosis is a common complication of colorectal cancer surgery with anastomosis. Transanal minimally invasive surgery is a novel approach to the treatment of anastomotic stenosis.This study aimed to evaluate the efficacy and safety of transanal minimally invasive surgery for anastomotic stenosis treatment.This was a retrospective study.This study was conducted at a comprehensive cancer center.This study included patients with rectal anastomotic stenosis who after undergoing colorectal surgery were admitted to the Sir Run Run Shaw Hospital between September 2017 and June 2019.The primary outcome was the operative success rate. The secondary outcomes were intraoperative variables, postoperative complications, stoma closure conditions, and stenosis recurrence risks.Nine patients, aged 52 to 80 years, with a history of colorectal cancer with end-to-end anastomosis underwent transanal minimally invasive surgery for anastomotic stenosis. The distance between the stenosis and the anal verge ranged from 5 to 12 cm. The mean stenosis diameter was 0.3 cm. Four patients had completely obstructed rectal lumens. Eight of 9 patients successfully underwent transanal minimally invasive surgery radial incision and cutting. The average operation time was 50 minutes. After the procedure, 1 patient had symptomatic procedure-associated perforations but recovered with conservative treatment. No perioperative mortality occurred. One patient underwent transverse colostomy 1 month after transanal minimally invasive surgery because of proximal colon ischemia induced by primary rectal surgery. Eight patients underwent protective loop ileostomy. After transanal minimally invasive surgery, stoma closure was performed in 88% of patients with no stenosis recurrence or obstruction at follow-up (21-42 mo).This study was limited by its small sample size and single-center design.Transanal minimally invasive surgery provides an excellent operative field, good maneuverability, and versatile instrumentation and is a safe and effective treatment for rectal anastomotic stenosis, especially for severe fibrotic stenosis or complete obstruction. See Dynamic Article Video at http://links.lww.com/DCR/B965 . more...

Recent interest in laparoscopic right colectomy with D3 lymphadenectomy for right colon cancer, has raised renewed attention to the anatomic variations of the gastrocolic trunk of Henlé (GTH). Understanding the vascular structure of the GTH region for individual patients should improve surgical outcomes. The goal of this nationwide multicenter study (Anatomical Classification of Henlé's Trunk in Laparoscopic Right Hemi-colectomy (HeLaRC) trial) was to study the anatomic patterns of the GTH region, to clarify the implications of GTH in laparoscopic right colectomy with D3 lymphadenectomy (D3-RC) and analyze their clinical significance.We enrolled 583 patients from 26 centers across China who underwent D3-RC. The number of tributaries, length and types of GTH constitutions and their influence on intra-operative data were investigated. A nomogram score (based on the length of GTH, body mass index (BMI), tumor location, T stage and type of GTH (type I vs. non-type I) was established to assess the potential hazard of bleeding.The GTH was found in 567 patients (97.3%). The distribution of GTH types was 0 (14.1%, n = 80), I (53.3%, n = 302), II (27.0%, n = 153), III (5.6%, n = 32). Of note, the type I GTH, T1 stage and tumor location at ileocecal or ascending colon were correlated with shorter exposure time of the GTH region (P 0.0001). Short length of GTH (P = 0.002) and tumor location (transverse colon vs. non transverse colon) (P = 0.003) were correlated with the amount of GTH bleeding during the surgery. Nomogram discrimination was good (C-index: 0.72 (95% CI: 0.64, 0.80)). The dissection plane was better in patients with type I GTH than with other types (P = 0.023).GTH pattern variations may affect surgical outcomes in patients undergoing D3-RC. Better recognition of GTH anatomy might lead to a safer operation with better oncologic quality. more...

BackgroundColorectal cancer (CRC) is one of the most prevalent malignances worldwide. However, CRC with situs inversus totalis (SCRC) is extremely rare, and molecular characterization of this disease has never been investigated.MethodsTumor tissue samples from 8 patients with SCRC and 33 CRC patients without situs inversus totalis (NSCRC) were subjected to multigene next-generation sequencing.ResultsThe most frequently mutated genes in SCRC were APC, TP53, CHEK2, MDC1, GNAQ, KRAS, and SMAD4. A high frequency of SCRC tumors had mutations in DNA damage repair genes. Single amino acid substitutions in the DNA damage repair genes caused by continuous double base substitution was identified in the majority of this population. Furthermore, mutational profiles showed notable differences between the SCRC and NSCRC groups. In particular, CHEK2, MDC1, GNAQ, SMAD4, BRCA1, HLA-B, LATS2, and NLRC5 mutations were more frequently observed in SCRC patients. The mutation loci distributions of KRAS in the SCRC cohort differed from that of the NSCRC cohort. Additionally, differences in the targeted genomic profiles and base substitution patterns were observed between the two groups.ConclusionsThese findings comprehensively revealed a molecular characterization of SCRC, which will contribute to the development of personalized therapy and improved clinical management of SCRC patients. more...

Background: Colorectal cancer (CRC) is associated with high mortality rates. Some studies have attempted to elucidate the molecular mechanisms underlying CRC, and few CRC biomarkers are now used in clinical practice. Methods: Herein our aim was to identify a new potential prognostic biomarker of CRC, while providing further theoretical basis for studying the pathogenesis of CRC. Results: PYCR2 expression was to be much higher in CRC tissues than in corresponding non-cancerous tissues, and the prognosis of patients with high PYCR2 expression was significantly poorer than that of those with low PYCR2 expression. Further, PYCR2 showed a high correlation with TRMT61B and CDC23 expression. We found that gene mutations had a significant influence on the prognosis of CRC. PYCR2 siRNA transfection decreased and inhibited the ability of migration and invasion in CRC cells. Conclusions: To summarize, our findings provide novel insights to facilitate better diagnosis as well as treatment of CRC. more...

Anastomotic leakage (AL) is a severe complication of rectal cancer low anterior resection (LAR). Ileostomy, the most common method to reduce the severity of AL, is associated with the risk of permanent stoma and an additional operation for stoma reversal. This purpose of this study is to develop a novel protective technique called the stent-based diverting technique (SDT) to protect the anastomosis following LAR.From March 2020 to December 2020, thirty-four patients treated with LAR followed by SDT were enrolled prospectively at Sir Run Run Shaw Hospital. Demographic characteristics, laboratory test results, surgical outcomes, and oncological features were recorded.Overall, the median period of stent degradation was 21 (18-24) days. One patient (2.9%) had anastomotic leakage, and another patient (2.9%) had intestinal obstruction, while no other complications (e.g., intestinal volvulus, perforation, fistula) were observed in this study.The unique SDT may be a novel approach to prevent anastomotic leakage following low anterior resection of rectal cancer. more...

Background: Sigmoid colon cancer is a common type of colon cancer; it refers to tumor lesions occurring in the segment approximately 16 cm to 50 cm from the anal margin. Currently, surgical resection is the most effective treatment for non-metastatic sigmoid colon cancer. Therefore, to more accurately standardize colon cancer surgery, we classified the sigmoid colon into distal and proximal segments. This study compares and analyzes the intraoperative situation, postoperative pathology and safety of radical resection of sigmoid cancer in different locations from different aspects. Result: The patients with sigmoid colon tumor can be divided into distal group (16-30cm from the anus) and proximal group (31-50cm from the anus) according to the distance between the tumor and the anal margin. Conclusion: The patients in the distal group using stapler for intestinal anastomosis and anal decompression tube were significantly more than those in the proximal group. For the ligation of the inferior mesenteric artery, high ligation was usually used or the left colic artery was usually preserved in the distal group, and the superior rectal artery was usually retained in the proximal group. The incidence of postoperative complications in the distal group was higher than that in the proximal group, but there was no significant difference between the two groups. more...

Hematopoietic stem cells (HSCs) reside in a quiescent niche to reserve their capacity of self‐renewal. Upon hematopoietic injuries, HSCs enter the cell cycle and encounter protein homeostasis problems caused by accumulation of misfolded proteins. However, the mechanism by which protein homeostasis influences HSC function and maintenance remains poorly understood. Here, we show that C/EBP homologous protein (CHOP), demonstrated previously to induces cell death upon unfolded protein response (UPR), plays an important role in HSCs regeneration. CHOP−/− mice showed normal hematopoietic stem and progenitor cell frequencies in steady state. However, when treated with 5‐FU, CHOP deficiency resulted in higher survival rates, associated with an increased number of HSCs and reduced level of apoptosis. In serial competitive transplantation experiments, CHOP−/− HSCs showed a dramatic enhancement of repopulation ability and a reduction of protein aggresomes. Mechanistically, CHOP deletion causes reduced ATF3 expression and further leads to decreased protein aggregation and ROS. In addition, CHOP−/− HSCs exhibited an increased resistance to IR‐induced DNA damage and improved HSCs homeostasis and function in telomere dysfunctional (G3Terc −/−) mice. In summary, these findings disclose a new role of CHOP in the regulation of the HSCs function and homeostasis through reducing ATF3 and ROS signaling., 5‐FU administration and hematopoietic stem cells (HSCs) transplatation induce high rate of protein synthesis and protein aggregation, which further cause impaired HSCs function. Under IR iradiation and telomere‐shortening induced DNA damage, C/EBP homologous protein (CHOP) deficiency protects HSCs from impairment. C/EBP homologous protein deletion reduces ATF3 expression, protein synthesis and rescues HSCs function through reduced ROS and cell apoptosis. more...

Ly6/Plaur domain‑containing 8 (LYPD8) contributes to the segregation of intestinal microbiota and intestinal epithelia and is critical for the prevention of intestinal inflammation. However, its relevance in cancer biology remains to be fully elucidated. The present study aimed to clarify the biological effects of LYPD8 on colon cancer tissue from patients and colorectal cancer (CRC) cells. The results revealed that the expression of LYPD8 was significantly reduced in the CRC tissue compared with that in precancerous tissue and normal tissue, particularly in stage III tissue. The results also revealed increased levels of P65 and signal transducer and activator of transcription 3 (STAT3) phosphorylation and increased secretion of interleukin‑6 (IL‑6) and tumor necrosis factor‑α (TNF‑α) in CRC tissue compared with levels in precancerous tissue. Supporting these findings, the levels of secreted TNF‑α and IL‑6 were significantly reduced when LYPD8 was overexpressed in human CRC cells, and the secretion of TNF‑α and IL‑6 were positively associated with the phosphorylation of STAT3 and P65. However, this trend was restored upon supplementation with TNF‑α and IL‑6 in CRC cells. Furthermore, the overexpression of LYPD8 in CRC cells significantly inhibited CRC cell proliferation and migration. Overall, the LYPD8‑mediated tumor‑inhibiting role involves a direct effect on the secretion of IL‑6/TNF‑α in CRC cells by reducing the phosphorylation of STAT3 and P65. more...

Background: 5-Fluorouracil (5-Fu) is the first-line chemotherapeutic drug in the treatment of colorectal cancer. The efficiency of 5-Fu is limited by drug resistance in colorectal cancer patients. This study was aimed to define the functions of tissue inhibitor metalloproteinases 2 (TIMP-2) in the 5-Fu resistance to colorectal cancer and investigate its potential mechanism.Methods: Cytokine array, ELISA and RT-qPCR were performed to detect cytokine expression levels. Western blot and immunohistochemistry were used to show the differential expression of proteins. In addition, cell viability was detected by CCK-8.Results: We established that there is an up-regulation in the expression of the TIMP-2 in colorectal cancer patients. This up-regulation in TIMP-2 expression was evident in 5-Fu resistant colorectal cancer patients and resulted in a poor prognosis. Besides, in vivo, clinical studies and patient-derived xenograft (PDX) models confirmed that TIMP-2 was highly expressed in the 5-Fu-resistant colorectal cancer. We deduced an autocrine mechanism through which elevated TIMP-2 protein levels sustained colorectal cancer cell resistance to 5-Fu by constitutively activating the ERK/MAPK signaling pathway via an autocrine mechanism. The 5-Fu resistance could overcome by the inhibition of TIMP-2 by anti-TIMP-2 antibody or ERK/MAPK by U0126.Conclusion: Our findings identify a TIMP-2-ERK/MAPK mediated 5-Fu resistance mechanism in colorectal cancer. Moreover, we recommend the use of an ERK/MAPK signal pathway inhibitor or TIMP-2-mediated immunotherapy for 5-Fu resistant colorectal cancer. more...

Rationale: A co-delivery system that can transport chemotherapeutic drugs and nucleotide drugs to distinct targets in tumors is an attractive strategy for cancer therapy. In this study, well-defined targeted quantum dot (QD)-based multifunctional nanocarriers were developed through self-assembly driven by host-guest interactions. 5-fluorouracil (5-FU) and microRNA-34a mimics (miR-34a(m)) were co-administered to achieve synergistic effects for colorectal cancer (CRC) therapy for the first time. Furthermore, the CRC patient-derived tumor xenograft (PDX) model, which closely mimics human CRC tumor pathological properties, was used for evaluating the therapeutic effect in this research. Methods: Multiple β-cyclodextrin (CD)-attached QD nanoparticles were used as host molecules. An adamantane (ADA)-modified TCP1 peptide-targeting ligand (TCP1) was used as the guest molecule. 5-FU and miR-34a(m) were loaded into TCP1-CD-QD nanocarriers, which were used to treat CRC in vitro and in vivo. In addition, the CRC PDX model was used to evaluate the treatment efficacy of this co-delivery system. Results: 5-FU and miR-34a(m) can be efficiently encapsulated into TCP1-CD-QD nanocarriers and delivered into CRC cells, which led to the inhibition of the proliferation and migration of CRC cells in vitro and suppression of tumor growth in a CRC cell-derived tumor xenograft model. The obtained data further suggested that co-delivery of 5-FU and miR-34a(m) could achieve synergistic effects for CRC therapy. Notably, targeted therapy via the co-delivery of 5-FU and miR-34a(m) by TCP1-CD-QD nanocarriers significantly inhibited the growth of PDX tumors. Conclusions: These studies strongly indicate that such a nanocarrier-based co-delivery system is a promising combined therapeutic strategy that utilizes chemotherapeutic drugs and nucleotide drugs for enhancing colorectal cancer targeting and synergistic therapy. more...

Rectal leiomyosarcoma is a rare neoplasm, and no standard therapeutic strategy has been established, other than surgical resection. The prognosis of advanced leiomyosarcoma in the rectum is poor. We describe a case of a 47-year-old man with a locally advanced rectal leiomyosarcoma who presented with anal bleeding and lower abdominal pain. After discussions by a multidisciplinary team (MDT), the patient received preoperative pelvic short-course radiotherapy followed by laparoscopic-assisted abdominoperineal resection. Adjuvant chemotherapy with doxorubicin and ifosfamide was administered postoperatively. Local recurrence was detected 13 months after the resection. The patient received chemotherapy with gemcitabine and docetaxel followed by radioactive particle implantation. Thereafter, apatinib was administered to gain systemic control. The patient died 24 months after the diagnosis. This case report draws attention to treatment with multidisciplinary therapy, as discussed by MDT, for rare locally advanced rectal leiomyosarcoma. more...

Ju, Z. et al. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat. Med. 13, 742–747 (2007). CAS Article Google Scholar De Cecco, M. et al. Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell. 12, 247–256 (2013). Article Google Scholar Murnane, J. P. & Sabatier, L. Chromosome rearrangements resulting from telomere dysfunction and their role in cancer. Bioessays 26, 1164–1174 (2004). CAS Article Google Scholar Niyongere, S. et al. Heterogeneous expression of cytokines accounts for clinical diversity and refines prognostication in CMML. Leukemia 33, 205–216 (2019). CAS Article Google Scholar Download references We thank the Dr. Jian Mao (School of Medicine, Hangzhou Normal University) for technical assistance. This work was supported by Grants 2016YFA0100602, 2017YFA0103302, 2018YFA0109300 from the National Key Research and Development Program of China; Grants 81525010, 91749203, 81871116, 81501214, 91749117, 81770155, and 81771502 from the National Natural Science Foundation of China; Grants LQ14C070002 from the Natural Science Foundation of Zhejiang Province of China; Grant 2018GZR110103002 from Innovative Team Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory and Grant 2017ZT07S347 from the Program for Guangdong Introducing Innovative and Enterpreneurial Teams. This work was supported by the Science Foundation for Distinguished Young Scholars of Guangdong Province (2019B151502008) to Hu Wang. These authors contributed equally: Ying Wang, Jin-ping Zheng Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, 311121, China Ying Wang, Junyi Wang, Lingjie Xu, Hu Wang & Zhenyu Ju Department of Public Health and Preventive Medicine, Changzhi Medical College, Changzhi, Shanxi, 046000, P. R. China Jin-ping Zheng Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China Ying Luo, Hu Wang & Zhenyu Ju CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China Jinyong Wang Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, 02903, USA John M. Sedivy Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China Zhangfa Song You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar Y.W., JP.Z., H.W., Y.L., JY.W., and LJ.X. carried out the experiments. Y.W., JP.Z., H.W., JinY W., J.M.S., ZF.S., and ZY.J. analyzed the data. Y.W., JP.Z., H.W., J.M.S., and ZY.J. wrote the paper. Correspondence to Ying Wang or Zhangfa Song or Hu Wang or Zhenyu Ju. The authors declare no competing interests. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Reprints and Permissions Wang, Y., Zheng, J., Luo, Y. et al. L1 drives HSC aging and affects prognosis of chronic myelomonocytic leukemia. Sig Transduct Target Ther 5, 205 (2020). https://doi.org/10.1038/s41392-020-00279-4 Download citation Received: 26 March 2020 Revised: 27 July 2020 Accepted: 30 July 2020 Published: 19 September 2020 DOI: https://doi.org/10.1038/s41392-020-00279-4 more...

Purpose5-Fluorouracil (5-Fu) is used as a conventional chemotherapy drug in chemotherapy for patients with advanced colorectal cancer, but many patients still suffer from treatment failure due to 5-Fu resistance. Emerging observations revealed the important role of chemokine (C-X-C motif) ligand 13 (CXCL-13) in tumor microenvironment and its relationship with prognosis in patients with colorectal cancer. This study is designed to reveal the important role of CXCL-13 in causing colorectal cancer resistance to 5-Fu.Materials and MethodsCXCL-13 levels of patient's serum or cell culture supernatants were measured separately by enzyme-linked immunosorbent assay. In cell assays, cell viability is detected by Cell Counting Kit-8. Therefore, the recombinant human CXCL-13 was used to simulate its high expression in cells while its antibody and siRNA were used to reduce CXCL-13 expression in cells.ResultsIn this study, we demonstrated that CXCL-13 is associated with 5-Fu resistance by culture medium exchange experiments and cytokine arrays of colorectal cancer resistant and nonresistant cells. Clinical studies showed that CXCL-13 is highly expressed in the serum of 5-Fu–resistant patients. High levels of serum CXCL-13 also predict a worse clinical outcome. The addition of recombinant CXCL-13 cytokine resulted in 5-Fu resistance, while its antibody overcame 5-Fu resistance, and knockdown of CXCL-13 expression by siRNA also reduced 5-Fu resistance, which can be saved by added recombination CXCL-13.ConclusionThese results not only identify a CXCL-13 mediated 5-Fu resistance mechanism but also provide a novel target for 5-Fu–resistant colorectal cancer in prevention and treatment strategies. more...

Telomere shortening represents a causal factor of cellular senescence. At the same time, several lines of evidence indicate a pivotal role of oxidative DNA damage for the aging process in vivo. A causal connection between the two observations was suggested by experiments showing accelerated telomere shorting under conditions of oxidative stress in cultured cells, but has never been studied in vivo. We therefore have analysed whether an increase in mitochondrial derived oxidative stress in response to heterozygous deletion of superoxide dismutase (Sod2(+/-)) would exacerbate aging phenotypes in telomere dysfunctional (mTerc(-/-)) mice. Heterozygous deletion of Sod2 resulted in reduced SOD2 protein levels and increased oxidative stress in aging telomere dysfunctional mice, but this did not lead to an increase in basal levels of oxidative nuclear DNA damage, an accumulation of nuclear DNA breaks, or an increased rate of telomere shortening in the mice. Moreover, heterozygous deletion of Sod2 did not accelerate the depletion of stem cells and the impairment in organ maintenance in aging mTerc(-/-) mice. In agreement with these observations, Sod2 haploinsufficiency did not lead to a further reduction in lifespan of mTerc(-/-) mice. Together, these results indicate that a decrease in SOD2-dependent antioxidant defence does not exacerbate aging in the context of telomere dysfunction. more...

As a key landmark during laparoscopic right colectomy, the classification and variation of the gastrocolic trunk of Henle (GTH) remains to be clarified. The aim of this nationwide multicenter study was to describe the characteristics of the GTH intra-operatively during laparoscopic right colectomies. Three hundred seventy-one patients who underwent laparoscopic right colectomies from January 2018 to March 2019 in 25 hospitals across China were enrolled in the study. The length of the GTH, the classification with a precise description of confluent tributaries, and other variations were analyzed. Of the 371 patients, 363 had a GTH. The proportion of type-0, type-I, type-II, and type-III was 15.2% (n = 55), 54.8% (n = 199), 25.3% (n = 92), and 4.7% (n = 17), respectively. The average length of the GTH was 8.5 mm, ranging from 2 to 30 mm. This is the first multicenter study with a large sample by which the GTH was classified based on laparoscopic intraoperative observation. Variations in the GTH were classified into four types based on the number of colic drainage veins (right colic, superior right colic, middle colic, accessory middle colic, and ileocolic veins), among which the right colic vein was the most common. The length of the GTH was relatively short, and thus might carry a risk of bleeding. Further clinical data should be correlated with the characteristics of the GTH. more...

Peritoneal dissemination is the most common condition of metastasis in gastric cancer. The survival duration of a patient with advanced stage gastric cancer, may be improved by gene therapy. In this study, we used an oncolytic adenovirus vector (Ad/TRAIL-E1) that expresses both the TRAIL and E1A genes under the control of a tumor-specific promoter. We evaluated the anti-tumor effect of Ad/TRAIL-E1 on gastric cancer cells in vitro, as well as in vivo in a xenograft peritoneal carcinomatosis mouse model. Our data showed that Ad/TRAIL-E1 induced TRAIL-mediated apoptosis in gastric cancer cell lines, but not in the normal cell lines. In addition, Ad/TRAIL-E1 significantly inhibited peritoneal metastasis and prolonged the survival of mice without treatment-related toxicity. Therefore, tumor-specific TRAIL expression from an oncolytic adenovirus vector may provide a novel therapeutic approach for the treatment of advance stage gastric cancer with peritoneal dissemination. more...

// Engeng Chen 1, 2 , Zhiru Zeng 3 , Bingjun Bai 1, 2 , Jing Zhu 1, 2 , Zhangfa Song 1, 2 1 Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, P.R. China 2 Key Laboratory of Biotherapy of Zhejiang Province, 310016, P.R. China 3 The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, P.R. China Correspondence to: Zhangfa Song, email: doctorsongzhangfa@163.com Keywords: CD133, CSCs, NSCLC, EGFR, meta-analysis Received: June 14, 2016 Accepted: July 19, 2016 Published: July 30, 2016 ABSTRACT The prognostic value of cancer stem cells (CSCs) marker CD133 in non-small-cell lung cancer (NSCLC) remains controversial. We performed this meta-analysis of 32 eligible studies to clarify the prognostic value of CD133 and provide evidence for CSCs hypothesis. We calculated pooled hazard ratio (HR) for survival outcomes and pooled odds ratio (OR) for clinical parameters associated with CD133 in total 3595 NSCLC patients by STATA. Our results showed that NSCLC patients with higher CD133 expression had shorter overall survival time only in Asian patients (HR = 3.80, 95% CI: 3.12–4.04, p < 0.001; I 2 = 32%) but not in Caucasian patients (HR = 1.15, 95% CI: 0.88–1.52, p = 0.307; I 2 = 0%), suggesting that differential prognostic value of CD133 in distinct ethnic group. We speculated that the intrinsic EGFR gene status of CSCs might be responsible for this racial difference. Additionally, we found that higher expression of CD133 was associated with poor differentiation (OR = 2.03, 95% CI: 1.32–3.14, p = 0.001) and lymph node metastasis (OR = 2.39, 95% CI: 1.62–3.52, p < 0.001) but there was no significant difference of CD133 expression between adenocarcinoma and squamous carcinoma (OR = 1.13, 95% CI: 0.93–1.38, p = 0.3) in NSCLC patients. These results may provide a new therapeutic perspective on the treatment of NSCLC patients according to the expression of CD133 in distinct ethnic group. more...

Angiogenesis is recognized as an important hallmark of cancer. Although telomerase is thought to be involved in tumor angiogenesis, the evidence and underlying mechanism remain elusive. Here, we demonstrate that human telomerase reverse transcriptase (hTERT) activates vascular epithelial growth factor (VEGF) gene expression through interactions with the VEGF promoter and the transcription factor Sp1. hTERT binds to Sp1 in vitro and in vivo and stimulates angiogenesis in a manner dependent on Sp1. Deletion of the mTert gene in the first generation of Tert null mice compromised tumor growth, with reduced VEGF expression. In addition, we show that hTERT expression levels are positively correlated with those of VEGF in human gastric tumor samples. Together, our results demonstrate that hTERT facilitates tumor angiogenesis by up-regulating VEGF expression through direct interactions with the VEGF gene and the Sp1 transcription factor. These results provide novel insights into hTERT function in tumor progression in addition to its role in telomere maintenance. more...

Fibroblasts have gained increasing attention in tissue desmoplasia, especially in tumors. Activated fibroblasts from various sources modulate matrix composition and stiffness associated with organ fibrosis as well as tumor progression. More importantly, cancer-associated fibroblasts (CAFs) interacts with both cancer cells and other stromal cells, providing a tumor-promoting microenvironment for tumor invasion and metastasis. However, CAF biology is not fully understood due to its heterogeneity. Here, we describe the main transforming cues that contribute to CAF activation and unveil the expanding CAF heterogeneity associated with tumor progression in multiple aspects. Finally, we summarize the prospective promising and challenging stroma-targeted anti-tumor strategies. more...

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Background: Although the absolute number of postoperative positive lymph nodes has been considered as one of the most important predictors for the survival of rectal cancer patients, many researchers have suggested that the lymph node ratio (LNR) may have a better predictive effect. After chemoradiotherapy for rectal cancer, the number of lymph nodes harvested is often reduced, and the predictive value of the postoperative LNR after chemoradiotherapy is still unclear. We performed a retrospective study to analyze the survival predictive value of the LNR after preoperative chemoradiotherapy for rectal cancer. Methods: Between January 2012 and December 2014, a total of 133 patients with locally advanced rectal cancer who underwent preoperative chemoradiotherapy followed by total mesorectal excision were reviewed. According to the postoperative pathological LNR, patients were divided into 3 groups, i.e., LNR = 0, 0 < LNR ≤ 0.15, and 0.15 < LNR ≤ 1, and patients with lymph node metastasis were divided into 2 groups, and the overall survival (OS) and disease-free survival (DFS) of each group were analyzed and evaluated. Results: The median follow-up time of this study was 40 months, and the 5-year OS and DFS rates were 86.3% and 74.8% for the whole cohort, respectively. According to the postoperative pathological LNR, patients were divided into 3 groups, LNR = 0, 0 < LNR ≤ 0.15, 0.15 < LNR ≤ 1, the respective 5-year OS and DFS rates for the LNR 3 groups were 96.7%, 94.7% and 42.9% (P < 0.001) and 84.9%, 73%, and 30.7% (P < 0.001), respectively. Multivariate analysis revealed that only the LNR was the independent prognostic factor for these patients. For patients with lymph node metastasis, it was also revealed that only the LNR was an independent prognostic factor. Subgroup analysis demonstrated that there was a significant correlation between the LNR and patient survival both in the number of lymph nodes harvested, less than 12 and more than 12 subgroups (P < 0.05). Conclusion: The postoperative positive lymph node ratio (LNR) is an independent prognostic factor for patients with locally advanced rectal cancer who undergo preoperative chemoradiotherapy followed by total mesorectal excision. Both in the number of lymph nodes harvested less than 12 and more than 12 subgroups, the LNR is significantly correlated with patient survival. more...

Progressive attrition of telomeres triggers DNA damage response (DDR) and limits the regenerative capacity of adult stem cells during mammalian aging. Intriguingly, telomere integrity is not only determined by telomere length but also by the epigenetic status of telomeric/sub‐telomeric regions. However, the functional interplay between DDR induced by telomere shortening and epigenetic modifications in aging remains unclear. Here, we show that deletion of Gadd45a improves the maintenance and function of intestinal stem cells (ISCs) and prolongs lifespan of telomerase‐deficient mice (G3 Terc −/− ). Mechanistically, Gadd45a facilitates the generation of a permissive chromatin state for DDR signaling by inducing base excision repair‐dependent demethylation of CpG islands specifically at sub‐telomeric regions of short telomeres. Deletion of Gadd45a promotes chromatin compaction in sub‐telomeric regions and attenuates DDR initiation at short telomeres of G3 Terc −/− ISCs. Treatment with a small molecule inhibitor of base excision repair reduces DDR and improves the maintenance and function of G3 Terc −/− ISCs. Taken together, our study proposes a therapeutic approach to enhance stem cell function and prolong lifespan by targeting epigenetic modifiers. more...

The liver possesses extraordinary regenerative capacity in response to injury. However, liver regeneration (LR) is often impaired in disease conditions. Wild-type p53-induced phosphatase 1 (Wip1) is known as a tumor promoter and enhances cell proliferation, mainly by deactivating antioncogenes. However, in this work, we identified an unexpected role of Wip1 in LR. In contrast to its known role in promoting cell proliferation in extrahepatic tissue, we found that Wip1 suppressed hepatocyte proliferation after partial hepatectomy (PHx). Deletion of Wip1 increased the rate of LR after PHx. Enhanced LR in Wip1-deficient mice was a result of the activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) pathway. Furthermore, we showed that Wip1 physically interacted with and dephosphorylated mTOR. Interestingly, inhibition of Wip1 also activated the p53 pathway during LR. Disruption of the p53 pathway further enhanced LR in Wip1-deficient mice. Therefore, inhibition of Wip1 has a dual role in LR, i.e., promoting hepatocyte proliferation through activation of the mTORC1 pathway, meanwhile suppressing LR through activation of the p53 pathway. However, the proregenerative role of mTORC1 overwhelms the antiproliferative role of p53. Furthermore, CCT007093, a Wip1 inhibitor, enhanced LR and increased the survival rate of mice after major hepatectomy. Conclusion: mTOR is a new direct target of Wip1. Wip1 inhibition can activate the mTORC1 pathway and enhance hepatocyte proliferation after hepatectomy. These findings have clinical applications in cases where LR is critical, including acute liver failure, cirrhosis, or small-for-size liver transplantations. (Hepatology 2015;61:2030-2041) more...

Antineoplastic platinum agents are used in first-line treatment of ovarian cancer, but treatment failure frequently results from platinum drug resistance. Emerging observations suggest a role of reactive oxygen species (ROS) in the resistance of cancer drugs including platinum drugs. However, the molecular link between ROS and cellular survival pathway is poorly understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we show that in platinum-resistant ovarian cancer elevated ROS levels sustain high level of IL-11 by stimulating FRA1-mediated IL-11 expression and increased IL-11 causes resistance to platinum drugs by constitutively activating JAK2–STAT5 via an autocrine mechanism. Inhibition of JAK2 by LY2784544 or IL-11 by anti-IL-11 antibody overcomes the platinum resistance in vitro or in vivo. Significantly, clinic studies also confirm the activated IL-11–JAK2 pathway in platinum-resistant ovarian cancer patients, which highly correlates with poor prognosis. These findings not only identify a novel ROS–IL-11–JAK2-mediated platinum resistance mechanism but also provide a new strategy for using LY2784544- or IL-11-mediated immunotherapy to treat platinum-resistant ovarian cancer. more...

The role of palliative primary tumor resection (PPTR) in improving survival in patients with synchronous unresectable metastatic colorectal cancer (mCRC) is controversial. In this study, we aimed to evaluate whether our novel scoring system could predict survival benefits of PPTR in mCRC patients.In this retrospective cohort study consecutive patients with synchronous mCRC and unresectable metastases admitted to Sir Run Run Shaw Hospital between January 2005 and December 2013 were identified. A scoring system was established by the serum levels of carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), neutrophil/lymphocyte ratio (NLR), and lactate dehydrogenase (LDH). Patients with scores of 0, 1-2, or 3-4 were considered as being in the low, intermediate, and high score group, respectively. Primary outcome was overall survival (OS).A total of 138 eligible patients were included in the analysis, of whom 103 patients had undergone PPTR and 35 had not. The median OS of the PPTR group was better than that of the Non-PPTR group, with 26.2 and 18.9 months, respectively (P < .01). However, the subgroup of PPTR with a high score (3-4) showed no OS benefit (13.3 months) compared with that of the Non-PPTR group (18.9 months, P = .11). The subgroup of PPTR with a low score (52.1 months) or intermediate score (26.2 months) had better OS than that of the Non-PPTR group (P < .001, P = .017, respectively).A novel scoring system composed of CEA, CA19-9, NLR, and LDH values is a feasible method to evaluate whether mCRC patients would benefit from PPTR. It might guide clinical decision making in selecting patients with unresectable mCRC for primary tumor resection. more...