SUBHAJIT ROY

ROLL NO. : BUR ZOO 2015/076

PAPER: MZJT 405
MOLECULAR BIOLOGY AND GENETICS
UNIVERSITY OF BURDWAN
PICTURE COURTESY: SUMAN DAS
 THE SAND PUPPY FOLKS
The sand puppy or naked mole rat (Heterocephalus glaber) is the inhabitant of
East Africa, where the longest lived rodent resides. They have the Mother Nature’s
own boon to treat. Till the date this phenomena is only discovered in naked mole
rat except two cases of adenocarcinoma from Brookfield zoo, Illinois.
 EARLY DAWN OF NAKED MOLE RATS

As published by Buffenstein, R. J,2004,

trials of introducing cancer to dozen of
naked mole rats at Barshop Institution were
trivially failed.

Using gamma irradiation

 SV40 mediated Ras mutated carcinoma

production by implanting deadly tumours

Uses as a MODEL OF HUMAN HEALTH and PHOTOGRAPH: Professor Rochelle Buffenstein from
the University of Texas with a naked mole rat
CANCER STUDY
 HYALURONATE CHOPPING LEADS
TO METASTASIS
 Hyaluronate matrix of ECM encapsulates cells to their defined
micro-environment.
 Hyaluronidase synthesized by malignant cells cleave off the matrix and passages
through basement membrane.
PECULARITIES IN HYALURONIC ACID
PRODUCTION: THE SUPER SUGAR
 Highly conserved Hyaluronate Synthase 2 (HAS 2) protein is substituted by two serines
from two conserved aspertates.
 Renders high processivity and synthesis of HIGH MOLECULAR MASS HYALURONATE
(HMM-HA).

COMPARATIVE MASS OF HYALURONATE POLYMERS IN DIFFERENT MAMMALS:

 EARLY CONTACT INHIBITION (ECI)
BY THE SUPER SUGARS
Tian et al. (2013), proved the role
Early Contact Inhibition (ECI) behind
the cancer resistance.

 ECI is regulated by the HA-CD44-

NF2 pathway.

HMM-HA binds to the cytoplasmic

membrane receptor CD44

Activation of tumour suppressor

protein Merlin encoded by the
Neurofibromatosis-2 gene (nf2).

Thereby cyclin dependent kinases

CDK4 and CDK6 are inhibited. Cell
cycle arrest is induced.
 pALT EXPRESSION IN ECI

In naked mole rats Merlin induced tumor suppressor genes expressed includes p15
and p16 fusion product pALT, that performs Early Contact Inhibition by effeciently
arresting cell cycle than that of p15 and p16 alone. Beside ARF tumour suppressor
also get expressed.
ASSOCIATED MOLECULAR INTERPLAY
 BLOCKING OF INDUCTION TO ANGIOGENESIS

 HINDRANCE TO Akt AND OSTEOPONTIN

ACTIVATION REGULATES METASTATIC CELL
SURVIVAL
 ASSOCIATED MOLECULAR INTERPLAY

 RESISTING Rho KINASE ACTIVATION CORRELATES TO PLANAR CELL MOTILITY

 TOLL LIKE RECEPTOR AND INFLAMMATORY SIGNAL:

Cancer cells can escape TLR 4 response but CD44-Hyaluronate interaction made the cells
susceptible to TLR attack.
 BLOCKING DOWN EMT
THUS FROM DIFFERENT ASPECTS EARLY CONTACT INHIBITION BLOCKS
EPITHELIAL TO MESENCHYMAL TRANSITIONS OF CANCER CELLS.
 WHY HUMANIZATION REQUIRED
As targeted cancer therapies often
confronts issues of drug resistance, so
natural strategies like Early Contact
Inhibition is need to be adopted in
therapeutics.
 FIRST HUMAN CELLS TO SYNTHESIZE
SUPER SUGARS.
First trial was performed by Tian et al.,
2013. They transfected cultures of human
fibroblasts with naked mole rat Has 2 gene
and the cells were successfully producing
super sugars in media.

Human cell lines expressing naked mole rat

HAS 2 is confirmed through immunoblot by
using anti HAS 2 antibody

Yet no in-vivo success has been achieved.

FIGURE : NAKED MOLERATHAS2 OVER-

EXPRESSED IN HUMAN HEK293 CELLS
HUMAN DNA WITHIN NAKED MOLE
RAT TUMOUR
Possibilities of using our own DNA to
produce cancer in naked mole rats will
open more pragmatic dimension of
research. As per Ryoji Ito,2012 reported
humanization of naked mole rats should
be focussed.
 FUTURE PROPOSITIONS
• Tissue specific conditional knockout/replacement with naked mole rat
Has 2 gene can be employed to treat tissue confined cancers.

• ECI can be adopted to treat early metastatic cancers.

 CONCLUSIONS

So, summing up all, we can draw conclusions:

 Naked mole rat has opened a new outlook of cancer therapy in nature’s own
accord not by any artificial strategy .
 Humanization efforts of Early Contact Inhibition should be practiced more at
the levels of therapeutics.
 Alongside by adopting such natural strategies we can subdue the effects of co-
evolutionary advantages of cancer cells i.e. drug resistance.
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