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Regulation of Hormone Secretion
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PTEN antagonises Tcl1/hnRNPK-mediated G6PD pre-mRNA splicing which contributes to hepatocarcinogenesis

Xuehui Hong1, Ruipeng Song1, Huiwen Song2

  • 1Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.

Gut
|December 20, 2013
PubMed
Abstract

Insights

The phosphatase and tensin homologue (PTEN) protein inhibits the pentose phosphate pathway (PPP) in liver cancer, but T cell leukaemia 1 (Tcl1) counteracts this effect. Targeting this axis may offer new therapies for hepatocellular carcinoma (HCC).

Area of Science:

  • Molecular biology and biochemistry of cancer signaling pathways.
  • Hepatocellular carcinoma (HCC) pathogenesis and therapeutics.

Background:

  • Epidemiological studies indicate that dysregulation of phosphatase and tensin homologue (PTEN) and T cell leukaemia 1 (Tcl1) signaling contributes to liver cancer development.
  • Understanding the PTEN/Tcl1 axis is crucial for deciphering hepatocellular carcinoma (HCC) mechanisms.

Purpose of the Study:

  • To elucidate the molecular and biochemical mechanisms by which the PTEN/Tcl1 axis regulates the pentose phosphate pathway (PPP) in hepatocellular carcinoma (HCC).
  • To investigate the role of PTEN and Tcl1 in controlling metabolic pathways critical for HCC progression.

Main Methods:

  • Comparative analysis of PTEN and glucose-6-phosphate dehydrogenase (G6PD) mRNA levels in human HCC and healthy liver tissues.
  • Measurement of PPP flux, glucose consumption, lactate production, NADPH levels, and lipid accumulation.
  • Utilized molecular biology, biochemistry, and mass spectrometry to study the PTEN/Tcl1 axis; assessed cell proliferation, apoptosis, senescence, and tumor formation in mice.

Main Results:

  • PTEN was found to inhibit the PPP, suppressing glucose consumption and biosynthesis in human liver tumors by binding to and preventing the dimerization of G6PD.
  • Tcl1 reversed PTEN's effects, promoting G6PD activity and expression via heterogeneous nuclear ribonucleoprotein K (hnRNPK)-dependent mechanisms; PTEN also inhibited G6PD splicing and inactivated Tcl1.
  • Tcl1 knockdown sensitized HCC to sorafenib, while G6PD knockdown inhibited hepatocarcinogenesis, highlighting their critical roles.

Conclusions:

  • The counteraction between PTEN and Tcl1 is a key regulator of the PPP in HCC.
  • Targeting the PTEN/Tcl1/hnRNPK/G6PD axis presents a potential therapeutic strategy for improving HCC patient prognosis.
  • This axis offers novel avenues for therapeutic intervention in hepatocellular carcinoma.
Keywords:
GLUCOSE METABOLISMHEPATOCELLULAR CARCINOMALIVER METABOLISMMOLECULAR BIOLOGYMOLECULAR MECHANISMS

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