Molecular biological analysis of 5-FU-resistant gastric cancer organoids; KHDRBS3 contributes to the attainment of features of cancer stem cell

Ukai, Shoichi; Honma, Reiko; Sakamoto, Naoya; Yamamoto, Yusuke; Pham, Quoc Thang; Harada, Kunyu; Takashima, Tsuyoshi; Taniyama, Daiki; Asai, Ryuichi; Fukada, Kaho; Naka, Kazuhito; Tanabe, Kazuaki; Ohdan, Hideki; Yasui, Wataru

doi:10.1038/s41388-020-01492-9

Cited by 44 publications

(34 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The present study showed the clinicopathological significance of KHDRBS3 expression in CRC and provided evidence that KHDRBS3 plays a pivotal role in acquiring essential characteristics of colorectal CSCs, especially in terms of multi‐drug resistance and anchorage‐independent proliferation. Although the molecular functions of KHDRBS3 have been reported in various tumors, 3,5,6 our results showed the biological and clinical significance of KHDRBS3 in CRC, which has not been reported to date, to our knowledge. CRCs have accumulated defects in oncogenes and tumor suppressor genes 11‐13 .…”

Section: Discussioncontrasting

confidence: 76%

“…Although previous studies have reported that KHDRBS3 is involved in the splicing of several genes including CD44 in breast cancer and GC, 5,6 no papers have detailed the biological function of KHDRBS3 in CRC. We tried to establish KHDRBS3 knockout CRC cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…4,5 We recently reported the upregulation of KHDRBS3 in patients with 5-FU-resistant gastric cancer (GC) and in organoids and its interaction with stem cell markers and multi-drug resistance associated protein 1 (MRP1). 6 CD44v promoted drug resistance and stemness of cancer cells via increased expression of MRP1. 6 Targeted knockout of KHDRBS3 significantly reduced the expression of CD44v and MRP1.…”

Section: Khdrbs3 (Kh Rna Binding Domain Containing Signalmentioning

confidence: 99%

“…6 CD44v promoted drug resistance and stemness of cancer cells via increased expression of MRP1. 6 Targeted knockout of KHDRBS3 significantly reduced the expression of CD44v and MRP1. 6 Although the importance of KHDRBS3 in tumor progression has been reported in various organs, no reports have detailed the functional role and clinical significance of KHDRBS3 in CRC.…”

Section: Khdrbs3 (Kh Rna Binding Domain Containing Signalmentioning

confidence: 99%

“…In addition to producing CD44v, KHDRBS3 has been reported to play a significant role in tumor progression, including increasing anoikis resistance in breast cancer and decreasing drug permeability in glioblastoma 4,5 . We recently reported the upregulation of KHDRBS3 in patients with 5‐FU‐resistant gastric cancer (GC) and in organoids and its interaction with stem cell markers and multi‐drug resistance associated protein 1 (MRP1) 6 . CD44v promoted drug resistance and stemness of cancer cells via increased expression of MRP1 6 .…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

KHDRBS3 promotes multi‐drug resistance and anchorage‐independent growth in colorectal cancer

et al. 2021

Self Cite

View full text Add to dashboard Cite

5‐Fluorouracil (5‐FU) is one of the most frequently used pharmacological agents in the treatment of colorectal cancer (CRC). Resistance to chemotherapy is a major cause of treatment failure of CRC, and it is a well known fact that cancer stem cells play a significant role in the acquisition of drug resistance. In this study, we focused on the KHDRBS3 gene that encodes KH RNA Binding Domain Containing, Signal Transduction Associated 3. We first clarified the relationship between KHDRBS3 and 5‐FU resistance. We then observed higher expression levels of KHDRBS3 in KRAS‐mutant organoids and cell lines in comparison with KRAS wild‐type organoids and cell lines. Immunohistochemical analysis using CRC cases revealed that the prognosis of KHDRBS3‐positive patients was significantly worse compared with that of KHDRBS3‐negative patients. Univariate and multivariate Cox proportional hazards analyses showed that KHDRBS3 was an independent prognostic factor in patients with CRC. We determined that KHDRBS3 might play a crucial role in the acquisition of stem cell properties, such as drug resistance and spheroid/organoid formation, by regulating CD44 variant expression and the Wnt signaling pathway. In an immunodeficient mouse model, KHDRBS3‐positive cells showed efficient tumor formation and formed metastatic lesions in the lungs. These results indicated that KHDRBS3 plays a crucial role in drug resistance and anchorage‐independent growth by maintaining stem cell‐like features in CRC cells. KHDRBS3 could be a promising candidate marker for predicting chemotherapeutic effect and prognosis in CRC patients.

show abstract

Section: Discussioncontrasting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Khdrbs3 (Kh Rna Binding Domain Containing Signalmentioning

confidence: 99%

Section: Khdrbs3 (Kh Rna Binding Domain Containing Signalmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

KHDRBS3 promotes multi‐drug resistance and anchorage‐independent growth in colorectal cancer

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

Chitosan‐Gelatin‐EGCG Nanoparticle‐Meditated LncRNA TMEM44‐AS1 Silencing to Activate the P53 Signaling Pathway for the Synergistic Reversal of 5‐FU Resistance in Gastric Cancer

et al. 2022

View full text Add to dashboard Cite

Chemoresistance is one of the leading causes of therapeutic failure in gastric cancer (GC) treatment. Recent studies have shown lncRNAs play pivotal roles in regulating GC chemoresistance. Nanocarriers delivery of small interfering RNAs (siRNAs) to silence cancer‐related genes has become a novel approach to cancer treatment research. However, finding target genes and developing nanosystems capable of selectively delivering siRNAs for disease treatment remains a challenge. In this study, a novel lncRNA TMEM44‐AS1 that is related to 5‐FU resistance is identified. TMEM44‐AS1 has the ability to bind to and sponge miR‐2355‐5p, resulting in the upregulated PPP1R13L expression and P53 pathway inhibition. Next, a new nanocarrier called chitosan‐gelatin‐EGCG (CGE) is developed, which has a higher gene silencing efficiency than lipo2000, to aid in the delivery of a si‐TMEM44‐AS1 can efficiently silence TMEM44‐AS1 expression to synergistically reverse 5‐FU resistance in GC, leading to a markedly enhanced 5‐FU therapeutic effect in a xenograft mouse model of GC. These findings indicate that TMEM44‐AS1 may estimate 5‐FU therapy outcome among GC cases, and that systemic si‐TMEM44‐AS1 delivery combined with 5‐FU therapy is significant in the treatment of patients with recurrent GC.

show abstract

The Role of Tumoroids in Cancer Research

Marzbali

Rezaei

2023

Interdisciplinary Cancer Research

View full text Add to dashboard Cite

Molecular biological analysis of 5-FU-resistant gastric cancer organoids; KHDRBS3 contributes to the attainment of features of cancer stem cell

Cited by 44 publications

References 22 publications

KHDRBS3 promotes multi‐drug resistance and anchorage‐independent growth in colorectal cancer

KHDRBS3 promotes multi‐drug resistance and anchorage‐independent growth in colorectal cancer

Chitosan‐Gelatin‐EGCG Nanoparticle‐Meditated LncRNA TMEM44‐AS1 Silencing to Activate the P53 Signaling Pathway for the Synergistic Reversal of 5‐FU Resistance in Gastric Cancer

The Role of Tumoroids in Cancer Research

Contact Info

Product

Resources

About